On December 4, 2018 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported its updated results from its ongoing Phase 1/2 AMELIA clinical trial of AUTO3 in patients with relapsed/refractory pediatric acute lymphoblastic leukemia (pALL) and its ongoing Phase 1/2 ALEXANDER clinical trial in patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, San Diego, California (Press release, Autolus, DEC 4, 2018, View Source [SID1234531874]). AUTO3 is a dual-targeted therapy incorporating two separate chimeric antigen receptors (CARs). Observations from preclinical studies indicate that AUTO3 independently targets CD19 and CD22. AUTO3 is designed to reduce relapse driven by antigen loss, a key defense mechanism used by the tumor cells and the primary cause of relapse in pALL.

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"The preliminary results of the AMELIA trial indicate that AUTO3, the first dual targeting CD19 and CD22 CAR T cell therapy under development for pediatric ALL, appears to have a manageable safety profile, with the potential to overcome target-negative relapse, a major limitation of current CD19-targeted therapies," said Professor Persis Amrolia, lead investigator and Consultant in Bone Marrow Transplant at Great Ormond Street Hospital (GOSH) and NIHR Research Professor of Transplantation Immunology at UCL Great Ormond Street Institute of Child Health (ICH).

"In the ALEXANDER trial, preliminary results indicate that AUTO3 followed by consolidation with a limited duration of anti-PD1 therapy appears to have a manageable safety profile at the doses evaluated. This is the first therapy that aims to address two emerging resistance mechanisms for non-Hodgkin lymphoma, target-negative relapse and checkpoint upregulation," said Dr. Anas Younes, Chief, Lymphoma Service at Memorial Sloan Kettering Cancer Center.

Simultaneous Targeting of CD19 and CD22: Phase 1 Trial of AUTO3, a Bicistronic Chimeric Antigen Receptor (CAR) T-cell Therapy, in Pediatric Patients with Relapse/Refractory B-cell Acute Lymphoblastic Leukemia (r/r B-ALL): AMELIA Trial (Abstract Number 279, oral presentation at 8:00AM on Sunday, December 2, 2018)

Dr. Amrolia reported on 10 patients with relapsed or refractory ALL who received an AUTO3 infusion as a single dose or split dose dependent on their tumor burden. Key inclusion criteria included age 1-24 years old with relapsed or refractory B-lineage ALL at high risk in first relapse or in second or greater relapse. Prior targeted therapies to CD19 and CD22 were not excluded. The average age of the 10 evaluable patients was 8.5 years, the median number of prior lines of therapy was 3. Product was successfully manufactured for all patients. AUTO3 was generally well tolerated with no ³ Grade 3 CRS, no ICU admission, and no pressors or critical care support for CRS required. One case of Grade 3 neurotoxicity was observed which was considered unlikely related to AUTO3 and primarily attributed to prior intrathecal chemotherapy. Grade 3 or higher cytopenias lasting at least 30 days were noted in 4 out of 10 patients. Among the 10 evaluable patients at all dose levels, 8 out of 10 achieved MRD negative CR and higher response rates were observed at doses ³3 x106/kg dose levels with all patients achieving MRD-negative remission. In the higher dose group, 4 out of 6 (67%) patients have an ongoing molecular CR and importantly, no loss of CD19 or CD22 was noted among relapsed patients. Initial data indicates response rates and persistence are dose dependant. Dose escalation is ongoing.

For more information about this trial and the inclusion criteria, visit www.ClinicalTrials.gov (NCT03289455).

Trial of AUTO3, the First Bicistronic Chimeric Antigen Receptor (CAR) Targeting CD19 and CD22, Followed By Anti-PD1 Consolidation in Patients with Relapsed/Refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL): Alexander Trial (Abstract Number 1679, poster presentation from 6:15 PM – 8:15PM on Saturday, December 1, 2018)

Dr. Kirit Ardeshna, principal investigator at University College London, UK, reported preliminary clinical data on safety and efficacy from this open-label, multi-center trial in patients with DLBCL treated with a single dose of AUTO3 followed by consolidation with anti-PD-1 antibody (pembrolizumab). Key inclusion criteria included histologically confirmed DLBCL, chemotherapy-refractory disease or relapse after at least two lines of therapy or after ASCT, and no prior allogeneic stem cell transplant. There were 7 patients evaluable for safety with at least 28 day follow up post-treatment. The median number of prior lines of therapy in these 7 evaluable patients was 3 (range was 2 to 4). All patients were treated at the starting dose of 50×106 transformed CAR T cells. Three patients received a consolidation with pembrolizumab, and 4 patients did not receive treatment with pembrolizumab. None of the treated patients developed CRS grade 3 or higher and one patient had neurotoxicity grade 3, considered possibly related to AUTO3. No dose limiting toxicities were observed and dose escalation continues. Six patients were evaluable for response, two achieved a CR and two a PR; two patients did not respond. The two CRs were ongoing at six and three months, respectively.

For more information about this trial and the inclusion criteria, visit www.ClinicalTrials.gov (NCT03287817).

About AUTO3

AUTO3 is a programmed T cell therapy containing two independent chimeric antigen receptors targeting CD19 and CD22 that have each been independently optimized for single target activity. By simultaneously targeting two B cell antigens, AUTO3 is designed to minimize relapse due to single antigen loss in patients with B cell malignancies. AUTO3 is currently being tested in two clinical trials, referred to as the AMELIA and ALEXANDER trials.

The AMELIA trial is a single-arm, open label, multi-center Phase 1/2 clinical trial of AUTO3 in patients up to 24 years of age with high-risk relapsed or refractory B-lineage. The trial also is enrolling patients who previously received CD19 or CD22 targeting therapies including other CAR T cell therapy. The primary objective for Phase 1 is to assess the safety and tolerability of AUTO 3 administration as well as to identify the Phase 2 dose and schedule. The purpose of this trial is to test the safety and efficacy, including the complete remission rate or minimal residual disease (MRD) negative response, of AUTO3. Autolus expects to enroll up to 54 patients in this trial.

The ALEXANDER trial is a single-arm, open label, multi-center Phase 1/2 clinical trial of AUTO3 in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). The primary objective for the Phase 1 portion is to assess the safety and tolerability of AUTO3 administration as well as to identify the recommended Phase 2 dose and maximum tolerated dose (MTD) of AUTO3. The purpose of this trial is to test the safety and efficacy, including the overall response rate as per Lugano criteria, of AUTO3 followed by limited duration of consolidation with anti-PD1 antibody. Autolus expects to enroll approximately 100 patients in this trial.

For more information about these trials and the inclusion criteria, visit www.ClinicalTrials.gov.

On December 4, 2018 Celgene Corporation (NASDAQ: CELG) reported results of the phase 3 AUGMENT study, which showed that REVLIMID (lenalidomide) in combination with rituximab (R2) demonstrated superior progression-free survival (PFS) in patients with relapsed/refractory indolent lymphoma compared to patients who received rituximab plus placebo (R-placebo) (Press release, Celgene, DEC 4, 2018, View Source [SID1234531825]). The data were presented by John Leonard, M.D. in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, C.A. (Abstract #445).

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The phase 3 randomized, double-blind, international clinical study evaluated the efficacy and safety of the investigational combination of R2 versus rituximab plus placebo in patients (n=358) with relapsed/refractory follicular (n=295) and marginal zone (n=63) lymphoma.

In the study, the R2 arm demonstrated a highly statistically significant improvement in the primary endpoint of progression-free survival (PFS), evaluated by an independent review committee, versus (vs.) the R-placebo arm. The median PFS was 39.4 months for patients treated with R2 and 14.1 months for those treated with R-placebo (P <0.0001; HR: 0.46; 95% CI, 0.34-0.62).

"The AUGMENT data, with R2 more than doubling progression-free survival over rituximab monotherapy, represents an important potential new treatment option for patients with relapsed/refractory follicular or marginal zone lymphoma," said John Leonard, M.D., AUGMENT lead investigator, The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology and director of the Joint Clinical Trials Office at Weill Cornell Medicine, who has also served as a consultant for Celgene.

Overall survival (OS), a secondary endpoint, showed a positive trend for improvement in the R2 arm vs. the control arm (16 vs. 26 death events) (HR: 0.61; 95% CI, 0.33-1.13). Two-year OS rate was 93% for patients receiving R2 and 87% for those receiving R-placebo.

Overall response rate (ORR), another secondary endpoint, was 78% (n=138) in the R2 arm vs. 53% (n=96) in the R-placebo arm, according to the independent review committee. Duration of response (DoR) was significantly improved for R2 vs. R-placebo with median DoR of 37 vs. 22 months, respectively (P =0.0015; HR: 0.53; 95% CI, 0.36-0.79).

The most frequent adverse event (AE) in the R2 arm was neutropenia (58%), vs. 22% in the R-placebo arm. Additional commonly observed AEs in more than 20% of patients included diarrhea (31% in the R2 arm vs. 23% in R-placebo), constipation (26% vs. 14%, respectively), cough (23% vs. 17%), and fatigue (22% vs. 18%), respectively. Adverse events that were reported at a higher rate (>10%) in the R2 arm were neutropenia, constipation, leukopenia, anemia, thrombocytopenia and tumor flare. No unexpected safety findings were observed in the AUGMENT trial.

"These data represent a potential new treatment strategy for patients with relapsed/refractory indolent non-Hodgkin’s lymphomas," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "We are advancing regulatory submissions in the first quarter of 2019 to bring this important combination to patients as soon as possible."

REVLIMID alone or in combination with other agents is not approved for use in follicular lymphoma or marginal zone lymphoma in any geography.

About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program.

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus

Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia.Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex or REVLIMID as maintenance therapy should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or dose reduction. Please see the Black Box WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and the regimen should be based on patient’s underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients with CLL: In a clinical trial in the first-line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of hematologic plus solid tumor SPM, notably AML and MDS, have been observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment

Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash, or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN, or DRESS is suspected and should not be resumed following discontinuation for these reactions

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before start of REVLIMID treatment and during therapy

Early Mortality in Patients with MCL: In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L)

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more Grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm
The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%)
After at least one prior therapy: The most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin

USE IN SPECIFIC POPULATIONS

PREGNANCY: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436
LACTATION: There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID
PEDIATRIC USE: Safety and effectiveness have not been established in pediatric patients
RENAL IMPAIRMENT: Adjust the starting dose of REVLIMID based on the creatinine clearance value and in patients on dialysis

On December 4, 2018 Portola Pharmaceuticals, Inc. (Nasdaq: PTLA) reported updated interim results from the Company’s ongoing Phase 2a study of cerdulatinib, an investigational, oral Syk/JAK inhibitor, in patients with specific subtypes of T-cell Non-Hodgkin Lymphoma, including relapsed/refractory peripheral T-cell lymphoma (PTCL); angioimmunoblastic T-cell lymphoma (AITL), a subset of PTCL; and cutaneous T-cell lymphoma (CTCL) (Press release, Portola Pharmaceuticals, DEC 4, 2018, View Source;p=RssLanding&cat=news&id=2379193 [SID1234531875]). The data will be presented today during an oral session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (December 1-4).

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As of the November 1, 2018 cut-off date, 41 PTCL patients and 27 CTCL patients were evaluable for response. The objective response rate (ORR) was 34 percent in the PTCL cohort and 26 percent in the CTCL cohort. Among the subset of patients in the PTCL cohort with AITL, the ORR was 57 percent.

PTCL Cohort Data

Eleven of 41 patients (27 percent) achieved a complete response (CR), and three patients (7 percent) achieved a partial response (PR).
In the subgroup of 14 patients with AITL, seven patients (50 percent) achieved a CR and one patient (7 percent) achieved a PR.
One patient who achieved a CR went on to transplant.
Eight responding patients have remained on drug for three to more than 12 months and five patients have had a duration of response of six months or greater. Follow-up is ongoing.
CTCL Cohort Data

In the CTCL cohort, two patients (7 percent) achieved a CR and five patients (19 percent) achieved a PR. Responses have been seen in patients with Mycosis Fungoides and Sezary Syndrome.
Eleven of 23 patients (48 percent) achieved a ≥ 50 percent reduction in skin lesions, based on the Modified Severity Weighted Assessment Tool (mSWAT).
Rapid improvements in pruritus, or severe itching – a common and often serious condition associated with CTCL – have been observed, as measured by the Likert scale.
The CTCL cohort continues to enroll and data analysis is ongoing.
Cerdulatinib has demonstrated tolerability in both PTCL and CTCL. The most common grade 3 or greater adverse events across the PTCL and CTCL cohorts with a frequency > 5 percent were lipase increase (23 percent), amylase increase (18 percent), sepsis/bacteremia (8 percent), and neutropenia, pneumonia/lung infection and diarrhea (7 percent each). These events are manageable and further accrual is ongoing.

"The ongoing Phase 2a cerdulatinib data continue to demonstrate meaningful clinical activity, with particularly compelling complete response rates among AITL patients and the potential for durable response among patients with PTCL and CTCL," said Steven M. Horwitz, M.D., Memorial Sloan Kettering Center, and study investigator. "Like many others with T-cell malignancies, the patients in this study have failed prior therapies and are in need of additional treatment options. It is encouraging to see such a strong early signal in both disease response and quality-of-life measures, such as itching."

"While still early, the continuing and durable response rates in PTCL and the encouraging responses in CTCL underscore the potential of cerdulatinib to control relapsed/refractory T-cell malignancies," said John Curnutte, M.D., Ph.D., executive vice president and head of research and development at Portola. "We will apply our learnings from this study to inform the design of a pivotal trial, and look forward to continuing discussions with the U.S. Food and Drug Administration about the potential for an accelerated approval pathway for cerdulatinib in PTCL."

ASH Oral Session Details – Monday, December 3, 2018 at 7:15 p.m. PST

Title: 1001. The Novel Syk/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability
and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral
T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

Session: 624 (Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: T Cell
Lymphoma: Chemotherapy and Targeted Approaches)

Presenter: Steven M. Horwitz, M.D., Memorial Sloan-Kettering Cancer Center

Session Time: 6:15 – 7:45 p.m. PST; Room 6F

About Cerdulatinib
Cerdulatinib is an investigational oral, dual spleen tyrosine kinase (Syk) and janus kinase (JAK) inhibitor that uniquely inhibits two key cell signaling pathways implicated in certain hematologic malignancies and autoimmune diseases. There is a strong rationale for inhibiting both Syk (B-cell receptor pathway) and JAK (cytokine receptors) in B-cell malignancies where both targets have been shown to promote cancer cell growth and survival. In addition, pre-clinical data suggest an important role for Syk and JAK in PTCL tumor survival.

The U.S. Food and Drug Administration granted cerdulatinib Orphan Drug Designation for the treatment of PTCL in September 2018.

On December 3, 2018 Genmab A/S (Nasdaq Copenhagen: GEN) reported that it will hold a R&D Update and 2018 ASH (Free ASH Whitepaper) Data Review Meeting today, December 3, 2016 at 8:00 PM Pacific Time (5:00 AM CET / 4:00 AM GMT on 4 December) (Press release, Genmab, DEC 3, 2018, View Source [SID1234531826]). The event will take place in San Diego, California, and will also be webcast live and archived on the company’s website. The meeting will include presentations by independent experts on data from daratumumab studies presented at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), including some key aspects of the Phase III MAIA study. Genmab speakers will also discuss pre-clinical data from Genmab’s DuoBody-CD3xCD20 and DuoHexaBody-CD37 programs presented at ASH (Free ASH Whitepaper), as well as the company’s progress and key goals for 2019.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The following cancer experts and senior Genmab staff will be at the event:

Independent experts:

Dr. Meletios A. Dimopoulos, National and Kapodistrian University of Athens, School of Medicine
Dr. Nizar Bahlis, Arnie Charbonneau Cancer Institute, University of Calgary
Dr. Saad Usmani, University of North Carolina at Chapel Hill, Levine Cancer Institute

Genmab:

Dr. Jan van de Winkel, President and CEO, Genmab
Dr. Judith Klimovsky, Executive Vice President and CDO, Genmab
Dr. Kate Sasser, Corporate Vice President, Translational Research, Genmab
Key daratumumab abstracts to be discussed during the event include:

LB-2: Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA)

Abstract 156: One-year Update of a Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Patients (Pts) With Transplant-ineligible Newly Diagnosed Multiple Myeloma (NDMM): ALCYONE

Abstract 151: Efficacy and Updated Safety Analysis of a Safety Run-in Cohort from GRIFFIN, a Phase 2 Randomized Study of Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone Versus Bortezomib, Lenalidomide, and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma Eligible for High-Dose Therapy and Autologous Stem Cell Transplantation

Abstract 1996: Three-Year Follow Up of the Phase 3 POLLUX Study of Daratumumab Plus Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone Alone in Relapsed or Refractory Multiple Myeloma

Abstract 3270: Efficacy and Safety of Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib, and Dexamethasone in First Relapse Patients: Two-Year Update of CASTOR

Abstract 1995: Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Safety and Efficacy Update of the Open-label, Multicenter, Phase 1b Study (PAVO)

The event will take place at the Manchester Grand Hyatt in San Diego, California, Harbor G&H. Those wishing to attend in person may register on site.

The event can also be attended via webcast. To view this webcast visit: View Source Webcast viewers may submit questions during the Q&A portion of the live webcast via the webcast player. An archive of the webcast will be available on Genmab’s website. The webcast will be conducted in English.

This meeting is not an official program of the ASH (Free ASH Whitepaper) Annual Meeting.

On December 3, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported its the long-term results of the Phase 3 ALCYONE study demonstrating that the addition of Darzalex (daratumumab) to bortezomib , melphalan and prednisone (VMP) continued to show significant improvement in progression-free survival (PFS) in patients recently diagnosed with multiple myeloma who are ineligible for autologous stem cell transplantation (GATS) (Press release, Johnson & Johnson, DEC 3, 2018, View Source [SID1234531843]). 1 These data ( Summary No. 156 ), as well as the updates of the LYRA ( Summary No. 152 ) and GRIFFIN ( Summary No. 151)) Phase 2 in patients with multiple myeloma were presented in an oral session on data presentation abstracts at the 60 th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) that was held in San Diego, California.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Long-term results of the ALCYONE Phase 3 trial for first-line combined treatment with daratumumab 1

With a median follow-up of 27.8 months, the results of the study showed that the addition of daratumumab to the combination of bortezomib, melphalan and prednisone (VMP) reduced the risk of disease progression by 57 percent. or death, in comparison with treatment based solely on the VMP combination (risk ratio [RR] = 0.43, 95 percent confidence interval [CI] 0.35-0.54, p <0, 0001). 1 The combination of daratumumab-VMP resulted in a 24-month PHC rate of 63 percent, compared to 36 percent for VMP alone. 1 The median PFS for the combination of araratumumab-VMP has not yet been reached, and the control group (PMV alone) had a median PFS of 19.1 months.1 In addition, a significantly higher overall response rate (91 percent vs. 74 percent, respectively) was observed for the combination based on daratumumab, compared with the single VMP. 1 The combination of daratumumab-VMP achieved faster responses, with a significant improvement in the rate of very good partial response or higher rate (73 percent versus 50 percent), and a strict complete response rate more than twice as high ( 22 percent vs. 8 percent) to that of the VMP alone. 1 The combination of aratumumab-VMP induced a higher rate of long-term residual residual disease negativity compared to VMP alone (10 percent versus 2 percent, respectively).1 The main results previously announced in this study motivated the European Commission to approve daratumumab in combination with MPV for patients with newly diagnosed multiple myeloma who are not eligible for GATS.

Long-term data from pivotal ALCYONE trial show that combined treatment with daratumumab continued to demonstrate improved progression-free survival and response rates in newly diagnosed patients with multiple myeloma, including patients older people less likely to respond to treatment, "said Meletios A. Dimopoulos, MD, professor and chair of the Clinical Therapies Department at the Faculty of Medicine at the National Capodistrian University of Athens, Greece, and principal investigator. These promising results support the use of daratumumab earlier in the treatment paradigm,

In the ALCYONE study, the most common grade 3/4 adverse events that occurred during treatment with daratumumab-VMP starting in cycle 10 included anemia (4 percent), neutropenia (2 percent), and bronchitis (1 percent). 1 No new safety concerns were observed, and Grade 3/4 infections remained treatable. 1

Data from LYRA and GRIFFIN Phase 2 trials support the efficacy and safety profile of daratumumab in newly diagnosed patients, including those who are eligible for high-dose treatment / GATS, and in patients in relapse 2 , 3

Response rates from the LYRA Phase 2 study were presented for the experimental use of daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients recently diagnosed with multiple and relapsed myeloma. 2 The overall response rate and TBRP or upper rate in 86 newly diagnosed patients, who were 79 and 44 percent, respectively, after 4 cycles, increased to 81 and 56 percent, respectively, at the end of the initial treatment period (average of 6 cycles). 2In addition, the TBRP or higher rate in 14 patients with recurrent multiple myeloma, which was 57 percent after 4 cycles, then increased to 64 percent at the end of induction, while the rate overall response remained stable at 71 percent (average of 7.5 cycles). 2 The 18-month PHC rate was 78 percent in newly diagnosed and ineligible autologous patients, compared with 53 percent in relapsed patients. 2 In addition, this study, which evaluated the fractionation of the first dose of daratumumab to reduce infusion duration on Day 1 of Cycle 1 (C1D1), demonstrated a safety profile consistent with previous studies. . 2Infusion reactions occurred in 49 percent of patients with C1D1, compared to four percent of patients on Day 2 of Cycle 1 (C1D2). Fifty-four percent of newly diagnosed patients experienced infusion reactions, the most common being: chills (14 percent), dyspnoea, pruritus, and nausea (8 percent each), as well as coughing. (7 percent). Fifty-seven percent of relapsed patients experienced infusion-related reactions, the most common of which were: cough (21 percent), hyperhidrosis, dyspnea and chills (7 percent each). Only two patients had a grade 3 infusion reaction, and no grade 4 infusion reaction occurred. has been noted. No interruption of taking daratumumab was necessary because of an infusion reaction. The median infusion time was 4.5 hours at C1D1, compared to 3.8 hours at C1D2.2 Grade 3/4 adverse events that occurred during treatment were reported in 56 percent of patients, the most common (≥10 percent) being neutropenia (13 percent). 2

Data presented in the GRIFFIN Phase 2 study evaluated daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) in a safety group of 16 patients recently diagnosed with multiple myeloma, eligible for high dose treatment and GATS. 3 The results showed that at the end of the GATS consolidation treatment, all patients who participated in the safety preparatory period achieved a TBRP or higher rate, and 63 percent of them achieved complete response (CR) or higher, with 25 percent of patients having achieved SCR. 3In addition, 94 percent of patients remained without progression during the study, at a median follow-up of 16.8 months. 3 In addition, 8 out of 16 patients (50 percent) were negative for the residual disease test, at a level of 10 -5 at the end of consolidation. 3 During grade 3/4 treatment, fourteen patients (88 percent) reported adverse events, including 10 cases (63 percent of patients) related to daratumumab treatment. 3The most common adverse events (≥10 per cent) that occurred during grade 3/4 treatment were neutropenia, pneumonia, thrombocytopenia, lymphopenia, febrile neutropenia, leukopenia, rash, and hypophosphatemia. 3 Thirteen patients (81 percent) had the following infections, all grades: upper respiratory infection (six patients), pneumonia (four patients), bronchitis (two patients), otitis and viral gastroenteritis (two patients each) ). 3 No deaths due to serious adverse events were reported and no patient had to discontinue treatment due to an adverse event. 3These data suggest that induction therapy with daratumumab has no negative impact on stem cell mobilization. All 16 patients had successful stem cell mobilization, followed by GATS. 3

"Daratumumab offers a consistent clinical benefit across multiple therapeutic lines for multiple myeloma, and positive data from the ALCYONE, LYRA, and GRIFFIN studies add to the solid body of evidence supporting daratumumab-based protocols," said Dr. Dr. Catherine Taylor, Head of Hematology Treatments for Europe, Middle East and Africa (EMEA) at Janssen-Cilag Limited. "These are important findings for patients that provide additional information about the most effective methods of managing care," she added.

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About the ALCYONE 4 trial

The randomized, open-label, multi-center Phase 3 ALCYONE (MMY3007) study enrolled 706 patients newly diagnosed with multiple myeloma and ineligible for high-dose GSC chemotherapy. The median age of these patients was 71 years (age range: 40-93). Patients were randomized to receive nine cycles of daratumumab combined with VMP, or VMP alone. In the daratumumab-VMP group, patients received 16 mg / kg of daratumumab once a week for the first week (cycle 1) and then once every three weeks (cycles 2-9). After nine cycles, they continued to receive 16 mg / kg of daratumumab once every four weeks until disease progression.

About the LYRA 5 trial

The ongoing, single-arm, open-label, multi-center LYRA (MMY2012) Phase 2 study enrolled 100 adult patients 18 years of age and older. Patients received 4-8 cycles of combination therapy with daratumumab, including an oral dose of cyclophosphamide 300 mg / m 2 on days 1, 8, 15 and 22; a subcutaneous dose of bortezomib 1.5 mg / m 2 on days 1, 8 and 15; a weekly oral or intravenous dose of dexamethasone 40 mg every 28 days. Daratumumab was administered at 8 mg / kg intravenously at days 1 and 2 of cycle 1, at a weekly dose of 16 mg / kg from cycle 1, at day 8 during cycle 2, at a dose of 16 mg / kg every 2 weeks at cycles 3-6, and at a dose of 16 mg / kg every 4 weeks at cycles 7-8. After the induction treatment, the patients were able to receive a GATS. All patients received 12 cycles of maintenance treatment of 16 mg / kg intravenously every 4 weeks.

About the GRIFFIN 6 trial

The randomized, open-label Phase II GRIFFIN study (MMY2004) recruited and treated more than 200 adults between 18 and 70 years of age, eligible for high-dose treatment / GATS, 7including 16 patients in the safety preparatory phase to evaluate the potential dose limiting toxicities during cycle 1 of daratumumab combined with VRd. The latter patients were treated with four cycles of daratumumab and VRd infusion every 21 days, followed by stem cell mobilization, high-dose treatment and GATS; two consolidation cycles with daratumumab and VRd; as well as maintenance therapy with daratumumab and lenalidomide at cycles 7-32. During induction and consolidation therapy (cycles 1-6), patients received an oral dose of 25 mg lenalidomide on days 1-14, a dose of 1.3 mg / m 2bortezomib subcutaneously on days 1, 4, 8 and 11 and a dose of 20 mg dexamethasone on days 1, 2, 8, 9, 15 and 16 every 21 days. An infusion of daratumumab 16 mg / kg IV was administered on days 1, 8 and 15 of cycles 1-4 and day 1 of cycles 5-6. During the maintenance period (cycles 7-32), patients received a daily dose of 10 mg lenalidomide (15 mg from cycle 10, if tolerated) on days 1-21 every 28 days, and an injection of daratumumab 16 mg / kg every 56 days; this treatment was adjusted every 28 days. Lenalidomide maintenance therapy can be extended beyond cycle 32, according to the local care protocol.7

About Daratumumab

Daratumumab is an advanced biological product targeting the CD38 gene, a surface protein that is overexpressed in multiple multiple myeloma cells, regardless of the stage of the disease. 8 The Daratumumab induce the death of tumor cells via multiple mechanisms of action immunologically mediated, including complement-dependent cytotoxicity (CDC), an antibody-dependent cellular cytotoxicity (CBDC) and dependent cellular phagocytosis of antibody (PCDA) and via apoptosis, during which a series of molecular steps inside the cell leads to the death of the cell. 9A subset of suppressive cells derived from myeloid, CD38 + regulatory T cells and CD38 + B cells was reduced by daratumumab. 9 Daratumumab is being evaluated as part of a comprehensive clinical development program covering a range of treatment protocols for multiple myeloma, including first-line treatment, or recurrence. 10,11,12,13,14,15,16,17 Additional studies are underway or planned to evaluate the potential of this treatment targeting other malignant and pre-malignant haematological conditions in which the CD38 gene is expressed, such as indolent myeloma. 18,19For more information, please visit www.clinicaltrials.gov .

In Europe, daratumumab is indicated for use in combination with bortezomib, melphalan and prednisone for the treatment of newly diagnosed adult patients with multiple myeloma who are ineligible for autologous stem cell transplantation as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, previously treated with a proteasome inhibitor and an immunomodulatory agent, and who experienced disease progression during the last treatment, and in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, and for the treatment of adult patients with multiple myeloma who have benefited fromat least one prior treatment.9 For more information on daratumumab, please see the summary of product characteristics at View Source .

In August 2012 , Janssen Biotech, Inc. and Genmab A / S entered into a worldwide agreement granting Janssen an exclusive license to develop, manufacture and market daratumumab. 20

About multiple myeloma

Multiple myeloma is an incurable cancer of the blood that is found in the bone marrow. The disease is characterized by excessive proliferation of plasma cells. 21 More than 45,000 new cases of multiple myeloma were diagnosed in Europe in 2016, and more than 29,000 patients died. 22 Up to half of newly diagnosed patients do not achieve five-year survival, 23 and nearly 29% of multiple myeloma patients die within one year of diagnosis. 24

Although the treatment may lead to remission, in most cases a relapse will occur because no cure is currently possible. 25 A refractory multiple myeloma is characterized by the fact that the patient’s disease progresses within 60 days following the last treatment. 26,27 A recurrent cancer is characterized by the fact that the disease recurs after a period of initial, partial or complete remission. 28While some patients with multiple myeloma have absolutely no symptoms, the majority of them are diagnosed with symptoms that may include bone problems, low blood counts, increased calcium levels, infections or kidney problems. 29 Patients who have relapsed after treatment with standard therapy, including inhibitors of the proteasome and immunumodulateurs agents have poor prognosis and few treatment options. 30