On December 7, 2020 Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (NYSE: LLY), reported clinical data from the LOXO-305 global Phase 1/2 BRUIN clinical trial in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, Eli Lilly, DEC 7, 2020, View Source [SID1234572323]). LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. These data are being presented in an oral presentation at the 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstract 542).

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"The data presented at ASH (Free ASH Whitepaper) reveal an incredibly encouraging and consistent safety and efficacy profile for LOXO-305 in heavily pre-treated CLL and SLL patients, regardless of previous therapies, reasons for discontinuations of those therapies, or presence of resistance mutations", said Anthony Mato, M.D., director of the CLL Program at Memorial Sloan Kettering Cancer Center and the presenting author. "We are increasingly in need of new therapies for patients that have been previously treated with a covalent BTK inhibitor, and LOXO-305 may allow us to continue treating patients in the same biologic class before attempting more complicated therapeutic approaches."

"The LOXO-305 data continue to surpass our expectations, and we are very excited for what these data could mean for patients with CLL and SLL", said David Hyman, M.D., chief medical officer of Loxo Oncology at Lilly. "These emerging data further substantiate our thesis that the drug’s reversible binding mode, high selectivity, and robust pharmacology offer a differentiated treatment option across B-cell leukemias and lymphomas. We are eager to initiate a Phase 3 program in 2021."

Key Data Presented at ASH (Free ASH Whitepaper)

As of September 27, 2020, 323 patients were enrolled in the study, including 170 with CLL/SLL, 61 with mantle cell lymphoma (MCL), 26 with Waldenström’s macroglobulinemia, and 66 with other B-cell lymphomas. The CLL/SLL patients had received a median of three prior lines of therapy with 86% receiving a prior BTK inhibitor, 90% an anti-CD20 antibody, 82% chemotherapy, 34% venetoclax, 21% a PI3K inhibitor, 6% CAR-T therapy and 2% an allogeneic transplant.

Pharmacokinetic analyses during the dose escalation demonstrated consistent dose-proportional exposures with low inter-patient variability across the entire dosing range of 25mg to 300mg daily. Doses of 100mg QD and greater exceeded BTK IC90 target coverage for the entirety of the dosing interval. Responses were observed starting at the first dose level.

The efficacy data presented at ASH (Free ASH Whitepaper) are based on investigator response assessments. Patients were considered efficacy-evaluable if they had at least one post-baseline response assessment or if they discontinued treatment prior to their first post-baseline response assessment. In 139 efficacy-evaluable patients with CLL/SLL treated across all dose levels, 88 responded including 69 partial responses (PR), 19 partial responses with ongoing lymphocytosis (PR-L), 45 stable disease (SD), one progressive disease (PD), five discontinued prior to their first response assessment and were considered non-evaluable (NE), resulting in an overall response rate (ORR) of 63% (95% CI: 55-71). The ORR was consistent in various subsets of patients, including:

In the 121 efficacy-evaluable BTK-pretreated patients, the ORR was 62% (95% CI: 53-71), rising to 84% (21/25) for those followed 10 months or more. This deepening of response over time is consistent with other BTK inhibitors and suggests the overall efficacy profile of LOXO-305 will continue to strengthen with additional follow-up.
The ORR was similar in patients who previously discontinued a covalent BTK inhibitor for progression (67% [53/79]) versus toxicity or another reason (52% [22/42]).
The ORR was also similar in those with a BTK C481 mutation (71% [17/24]) and those without (66% [43/65]).
In patients who previously received prior chemoimmunotherapy, a covalent BTK inhibitor and a BCL-2 inhibitor the ORR was 69% (27/39).
In patients who previously received all five classes of available CLL/SLL therapy including prior chemoimmunotherapy, a covalent BTK inhibitor, a BCL-2 inhibitor, and a PI3K inhibitor the ORR was 58% (7/12).
In the 28 patients with a 17p deletion, TP53 mutation, or both, the ORR was 79% (22/28).
As of the data cut-off, 88% of all CLL/SLL patients remain on LOXO-305. Median follow-up for efficacy-evaluable CLL/SLL patients was six months. Of the 88 responding CLL/SLL patients, all except five remain on therapy (four progressed and one achieved a PR and electively discontinued to pursue a transplant). The longest-followed responding patient continues on treatment at 17.8 months.

Safety data were presented for the entire enrolled BRUIN population. Across all 323 patients enrolled in the study, the most commonly reported adverse events, regardless of attribution, were fatigue (20%), diarrhea (17%), and contusion (13%). In addition, rates of two adverse events commonly associated with BTK inhibitors, atrial arrythmias and hemorrhage, were low, experienced by two patients and one patient respectively, and considered by investigators as unrelated to LOXO-305. Dose interruptions, reductions and permanent discontinuations for drug-related adverse events were observed in 8%, 2.2%, and 1.5% of patients, respectively. No dose limiting toxicities were reported and a maximum tolerated dose (MTD) was not reached.

LOXO-305 Development Program Update

In addition to the previously announced Phase 3 MCL trial, Loxo Oncology at Lilly is preparing to initiate two global, randomized, Phase 3 clinical trials in BTK pre-treated patients with CLL/SLL. The trials will explore LOXO-305, alone and in combination as follows:

BRUIN CLL-321: CLL/SLL patients who progressed or were intolerant to covalent BTK inhibitor treatment will be randomized to receive continuous LOXO-305 therapy or investigator’s choice of either Idelalisib plus Rituximab or Bendamustine plus Rituximab. This trial is expected to start in the first quarter of 2021.
BRUIN CLL-322: CLL/SLL patients who progressed or were intolerant to covalent BTK inhibitor treatment will be randomized to receive a time-limited combination of either LOXO-305 plus venetoclax and Rituximab or venetoclax and Rituximab. This trial is expected to start in the second quarter of 2021.
In addition, Loxo Oncology at Lilly is planning to study LOXO-305 in treatment-naïve CLL/SLL, including a global, randomized Phase 3 superiority clinical trial to study LOXO-305 versus ibrutinib, expected to start later in 2021.

About LOXO-305
LOXO-305 is an investigational, oral, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma. Currently available BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies can be limited by acquired resistance, most commonly through BTK C481 mutations. In rapidly growing tumors with inherently high rates of BTK turnover, resistance to covalent BTK therapies may be the result of incomplete target inhibition. LOXO-305 was designed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. Interested patients and physicians can contact the Loxo Oncology at Lilly Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email [email protected].

About the BRUIN Trial
This first-in-human, global, multi-center Phase 1/2 trial evaluates LOXO-305 as a single agent in patients with previously treated chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin’s lymphomas (NHL). The trial includes a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The Phase 1 dose escalation enrolls patients with CLL/SLL or NHL who have received at least two prior lines of therapy and have progressed or are intolerant to standard of care. The dose escalation phase followed a "3+3" design with LOXO-305 dosed orally in 28-day cycles. As dose cohorts were cleared, additional patients could enroll in cleared cohorts and intra-patient dose escalation was permitted. The primary objective of the Phase 1 portion of the trial is to determine the maximum tolerated dose and recommended Phase 2 dose. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Overall Response Rate (ORR) and Duration of Response, as determined by appropriate histology-specific response criteria). In the Phase 2, patients are enrolled across various cohorts, depending on disease type and prior therapy. The primary endpoint for Phase 2 is ORR. Secondary endpoints include duration of response (DOR), overall survival (OS), safety, and pharmacokinetics (PK).

About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.

On December 7, 2020 Seagen Inc. (Nasdaq:SGEN) reported multiple ADCETRIS (brentuximab vedotin) data presentations at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place virtually December 5-8, 2020 (Press release, Seagen, DEC 7, 2020, View Source [SID1234572321]). Data presentations include five-year updates from the phase 3 ECHELON-1 and ECHELON-2 clinical trials evaluating ADCETRIS plus a chemotherapy combination regimen in frontline advanced stage classical Hodgkin lymphoma (HL) and CD30-expressing frontline peripheral T-cell lymphoma (PTCL), respectively. In addition, first results were presented from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with Opdivo (nivolumab) in relapsed or refractory mediastinal gray zone lymphoma (MGZL), a rare type of non-Hodgkin lymphoma that express CD30 with no standard of care. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL and expressed on the surface of several types of non-Hodgkin lymphoma, including PTCL. ADCETRIS is being evaluated globally in more than 70 corporate- and investigator-sponsored clinical trials across multiple settings in lymphoma and other indications. ADCETRIS and Opdivo are not approved alone or in combination for the treatment of relapsed or refractory MGZL.

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"After five years of follow-up, an important clinical milestone, both the ECHELON-1 and ECHELON-2 clinical trials demonstrate that ADCETRIS plus chemotherapy resulted in superior and durable outcomes when compared with standard chemotherapy regimens," said Roger Dansey, M.D., Chief Medical Officer at Seagen. "As most relapses in Hodgkin lymphoma occur within five years of frontline treatment, the results of the ECHELON-1 study suggest that patients treated with ADCETRIS plus chemotherapy are more likely to experience long-term remissions compared to those treated with the ABVD regimen."

Brentuximab Vedotin with Chemotherapy for Patients with Previously Untreated, Stage III/IV Classical Hodgkin Lymphoma: 5-Year Update of the ECHELON-1 Study (Abstract #2973, poster presentation on Monday, December 7, 2020)

The ECHELON-1 clinical trial is evaluating ADCETRIS in combination with AVD (Adriamycin [doxorubicin], vinblastine, dacarbazine) compared to ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) in patients with Stage III or IV frontline classical HL. As previously reported, the ECHELON-1 trial achieved its primary endpoint with the combination of ADCETRIS plus AVD resulting in a statistically significant improvement in modified progression-free survival (PFS) compared to the control arm of ABVD as assessed by independent review facility (IRF; hazard ratio (HR), 0.77; p=0.035). A five-year exploratory analysis was conducted to examine PFS outcomes per investigator assessment in the intent-to-treat population of 1,334 patients. Results include:

Patients in the ADCETRIS plus AVD arm had a 32 percent reduction in the risk of a progression event compared to patients in the ABVD arm. The five-year PFS rate for patients in the ADCETRIS plus AVD arm was 82.2 percent compared to 75.3 percentin the ABVD arm, an absolute difference of 6.9 percent (HR, 0.681 [95% CI: 0.534, 0.867]). Median follow-up time was 60.9 months.
Consistent benefit in PFS was observed among patients treated with ADCETRIS plus AVD compared with ABVD, independent of disease stage, age and prognostic score.
Consistent improvements compared to ABVD were observed in patients with Stage III (HR, 0.593; [95% CI: 0.385, 0.915]) and Stage IV (HR, 0.731; [95% CI: 0.545, 0.980]) disease.
As previously reported for the primary analysis, on the ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 67 percent of patients compared to 43 percent in the ABVD arm. The five-year update shows that among patients with peripheral neuropathy, 85 percent in the ADCETRIS plus AVD arm and 86 percent in the ABVD arm reported complete resolution or improvement at last follow-up.
There were fewer secondary malignancies in the ADCETRIS plus AVD arm. Among 48 patients with reported secondary malignancies, 19 [(nine hematological malignancies and 10 solid tumors)] were in the ADCETRIS plus AVD arm and 29 [(15 hematological malignancies and 14 solid tumors)] were in the ABVD arm.
There were a higher number of pregnancies in the ADCETRIS plus AVD arm compared to the ABVD arm. A total of 150 pregnancies were reported among study participants and their partners, including 89 on the ADCETRIS plus AVD arm and 61 on the ABVD arm.
The ECHELON-2 Trial: 5-Year Results of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in Frontline Treatment of Patients with CD30-Positive Peripheral T-Cell Lymphoma (Abstract #1150, poster presentation on Saturday, December 5, 2020)

The ECHELON-2 clinical trial is evaluating ADCETRIS in combination with CHP (cyclophosphamide, Adriamycin [doxorubicin], prednisone) compared to CHOP (cyclophosphamide, Adriamycin [doxorubicin], vincristine, prednisone) in frontline CD30-expressing PTCL. As previously reported, the ECHELON-2 trial met its primary endpoint with the combination of ADCETRIS plus CHP resulting in a statistically significant improvement in PFS versus the control arm of CHOP per blinded independent central review (HR, 0.71; p=0.0110). A five-year post-hoc exploratory analysis was conducted to examine PFS outcome and overall survival (OS) per investigator assessment in the intent-to-treat population of 452 patients. Key findings include:

Patients in the ADCETRIS plus CHP arm had a 30 percent reduction in the risk of a progression event compared to patients in the CHOP arm. The five-year PFS rate for patients in the ADCETRIS plus CHP arm was 51.4 percent compared to 43 percent in the CHOP arm, an absolute difference of 8.4 percent (HR, 0.70 [95% CI: 0.53, 0.91]).
OS in the ADCETRIS plus CHP arm was improved compared to CHOP (HR=0.72 [95% CI: 0.53, 0.99]). This represents a 28 percent reduction in the risk of death. Median follow-up time was 66.8 months.
Among 316 systemic anaplastic large-cell lymphoma (sALCL) patients on study, patients in the ADCETRIS plus CHP arm had a 45 percent reduction in the risk of a progression event compared to patients in the CHOP arm (HR, 0.55 [95% CI: 0.39, 0.79]). There was a 34 percent reduction in the risk of death. Median follow-up time for PFS was 42.7 months.
Consistent improvement in both PFS and OS was observed among patients treated with ADCETRIS plus CHP arm compared to the CHOP arm across the majority of pre-specified subgroups.
The five-year update shows that among patients with peripheral neuropathy, 72 percent in the ADCETRIS plus CHP arm and 78 percent in the CHOP arm reported complete resolution or improvement at last follow-up. For ongoing peripheral neuropathy events, 98 percent in the ADCETRIS plus CHP arm and 98 percent in the CHOP arm were Grade 1 or 2.
Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study (Abstract #2045, poster presentation on Sunday, December 6, 2020)

Data from the ongoing CheckMate 436 phase 2 clinical trial of 10 patients with relapsed or refractory MGZL who received a combination of ADCETRIS plus Opdivo treatment after autologous stem cell transplant or two or more lines of multi-agent chemotherapy if ineligible for transplant will be presented for the first time. Patients were treated once every three weeks or until disease progression or unacceptable toxicity. The median age of patients was 35 years. Key findings include:

Of 10 response-evaluable patients, seven patients (70 percent) had an objective response, including five patients (50 percent) with a complete response and two patients (20 percent) with a partial response. Two patients (20 percent) had progressive disease and in one patient (10 percent) death occurred prior to disease assessment.
Median follow-up time was 12.4 months. Time to complete response was 1.2-4.8 months and the duration was 1.5+ to 3.2+ months before patients were assessed for subsequent therapy. All patients who achieved a complete response underwent a hematopoietic cell transplant and follow-up is ongoing.
The most common adverse events of any grade in at least 20 percent of patients were neutropenia and paresthesia (30 percent each); thrombocytopenia, anemia and peripheral sensory neuropathy (20 percent each). The most common Grade 3 adverse events were neutropenia and thrombocytopenia (10 percent each). Three patient deaths occurred due to disease progression.
About ADCETRIS

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing cells.

ADCETRIS for injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions in 2013 for patients with (1) HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and (2) sALCL after failure of at least one multi-agent chemotherapy regimen. Non-conditional approval was granted for (3) post-ASCT consolidation treatment of patients with HL at increased risk of relapse or progression in 2017, (4) adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy in 2018, (5) for previously untreated patients with Stage IV HL in combination with doxorubicin, vinblastine, and dacarbazine in 2019, and (6) for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with doxorubicin, vinblastine and dacarbazine (AVD), (2) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (3) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (4) for the treatment of adult patients with previously untreated sALCL in combination with cyclophosphamide, doxorubicin and prednisone (CHP), (5) for the treatment of adult patients with relapsed or refractory sALCL, and (6) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in more than 70 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See U.S. important safety information, including Boxed Warning, below.

Seagen and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Administer G-CSF primary prophylaxis beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Most Common (≥20% in any study) Adverse Reactions

Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

On December 7, 2020 TG Therapeutics, Inc. (NASDAQ: TGTX), reported two triple therapy combination data presentations (Press release, TG Therapeutics, DEC 7, 2020, View Source [SID1234572320]). The first evaluated the investigational combination of umbralisib plus ublituximab (U2) plus venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL); and the second evaluated the investigational combination of U2 plus TG-1701, the Company’s once daily, oral, BTK inhibitor, in patients with R/R CLL or B-cell lymphoma. Data from these trials were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting and exposition. Presentation highlights are included below.

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated, "We are extremely pleased by the triple therapy data presented today demonstrating the potential of U2 with both venetoclax and our BTK inhibitor, TG-1701." Mr. Weiss continued, "Our mission continues to be to drive toward better outcomes for patients with B-cell malignancies by developing multi-drug combinations. We believe the data with these triple combinations highlights our approach of leveraging our portfolio and standard of care therapies to build on the U2 backbone with the goal of creating potentially best in class treatments for patients in need."

PRESENTATION HIGHLIGHTS:

Poster Presentation Title: A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax (U2-Ven) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Regimen was administered with 3 cycles of U2 as induction in cycles 1 through 3, U2 plus venetoclax in cycles 4, 5 and 6, followed by umbralisib plus venetoclax in cycles 7 through 12 in patients with R/R CLL. Patients with centrally confirmed undetectable minimal residual disease (uMRD) in the bone marrow after cycle 12 were permitted to stop all therapy, while MRD detectable patients continued on single agent umbralisib.
43 patients have been treated as of the data cutoff with 58% of patients previously exposed to a BTK inhibitor
Among evaluable patients, ORR was 77% (30/39) after cycle 3 (U2 only), 100% (31/31) after cycle 7, and 100% (27/27) after cycle 12
Among the 27 patients who finished 12 cycles of therapy:
• 41% achieved Complete Response (CR) by iwCLL criteria
• 96% achieved undetectable MRD in the peripheral blood
• 77% achieved undetectable MRD in the bone marrow
At a median follow up of 15.6 months (n=43), only 1 patient has progressed 10 months after stopping treatment
Grade 3/4 adverse events occurring in > 5% of patients were neutropenia (21%), leukopenia (12%), infusion related reactions (7%), anemia (5%), and diarrhea (5%). No TLS events were observed during venetoclax administration, with one TLS event occurring prior to venetoclax administration.
Poster Presentation Title: Clinical Activity of TG-1701, As Monotherapy and in Combination with Ublituximab and Umbralisib (U2), in Patients with B-Cell Malignancies

A total of 102 patients with R/R CLL or b-cell lymphoma have been treated with TG-1701, with patients receiving monotherapy in the dose-escalation cohort (n=25) or in the 200 mg dose-expansion cohort (n=61), or TG-1701 in combination with U2 in the dose escalation cohort (n=16)
TG-1701 monotherapy was well tolerated and the maximum tolerated dose was not reached up through 400 mg QD
Grade 3/4 adverse events (AE) occurring in >10% of patients treated with TG-1701 monotherapy were limited and included ALT increase (12%), all of which were patients treated with 400 mg QD. At the target single-agent Phase 2 dose of 200mg (QD) (n=61), AEs of special interest included Grade 3 hypertension (1.6%), atrial fibrillation (1.6%), and no instances of major bleeding observed. Grade 3/4 AEs occurring in >10% of patients treated with U2+1701 were ALT increase (25%), AST increase (19%) and neutropenia (12%).
At a median follow up of 7 months in the 200 mg QD monotherapy expansion cohorts, preliminary overall response rates (ORR) were: 95% (19/20) in CLL, 50% (6/12) in mantle cell lymphoma (MCL), and 95% (18/19) in Waldenstrom macroglobulinemia (WM)
At a median follow up of 12 months, the 1701+U2 dose escalation (using doses of 100mg to 300 mg QD of TG-1701) resulted in 79% ORR, with 22% CR rate across patients with WM, CLL, marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (n=14)
Data presented at ASH (Free ASH Whitepaper) 2020 will be available on the Publications page of the Company’s website at View Source

CONFERENCE CALL REPLAY INFORMATION
The Company hosted a conference call on November 5, 2020, with leading investigators from the UNITY-NHL and UNITY-CLL trials to discuss the data included in the ASH (Free ASH Whitepaper) 2020 abstracts. A recording of the conference call is available for replay at View Source

On December 7, 2020 Teneobio, Inc., a clinical stage biotech company focused on discovery and development of novel multi-specific biotherapeutic antibodies, reported initial results of a Phase I trial (View Source) evaluating TNB-383B in Relapsed Refractory Multiple Myeloma (R/R MM) on December 5 at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Conference (Press release, TeneoBio, DEC 7, 2020, View Source;utm_medium=rss&utm_campaign=teneobio-reports-initial-data-phase-study-of-tnb-383b-in-relapsed-refactory-multiple_myeloma [SID1234572319]). TNB-383B is a fully human bispecific antibody that targets BCMA on the surface of multiple myeloma (MM) cells and CD3 on the surface of T cells in order to trigger lysis of MM cells in MM patients. The ongoing open-label multi-center trial is designed to assess the safety, pharmacokinetics and preliminary efficacy of TNB-383B administered intravenously once every 21 days.

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TNB-383B demonstrated a favorable safety profile in patients with R/R MM and achieved an overall response rate (ORR) of 80% at doses ≥ 40 mg every three weeks (QW3). The most common adverse events were cytokine release syndrome (CRS), fatigue, headache, anemia, infection, and nausea. Notably, at all doses, CRS was limited to Grade 1-2, with no patient experiencing a Grade 3 CRS. No step-dosing or dose splitting was necessary in any patient. Among the responders, over 75% had very good partial response (VGPR) or better. The median Time to Response (TTR) was 3 weeks (1 cycle) and responses deepened with additional time on therapy. The multi-center escalation and expansion cohorts are ongoing so that the median Duration of Response (DOR) has not been reached.

"Immunotherapy represents the next frontier in the management of myeloma, with many different approaches being explored in clinical trials. The results with TNB-383B have been very promising with high response rates in patients with relapsed refractory myeloma and very manageable toxicity that allows for outpatient management of these patients," said Dr. Shaji Kumar of Mayo Clinic, Rochester, and one of the Principal Investigators on this trial. "We are pleased to announce these compelling initial results. The safety profile and response rates we have seen in this initial trial validate our differentiated CD3 platform and support further development of TNB-383B in R/R MM patients," said Ben Buelow, Teneobio’s Chief Medical Officer. "In addition to TNB-383B, we look forward to advancing multiple CD3 engaging bi-specific antibodies into the clinic, both in hematologic malignancies and solid tumors."

About TNB-383B

TNB-383B is a fully human bispecific monoclonal antibody being developed for MM. TNB-383B was designed to bind to BCMA with high affinity and simultaneously result in T-cell binding/activation to cause destruction of tumor cells accompanied by markedly attenuated cytokine production. TNB-383B is being developed in collaboration with AbbVie Inc.

On December 7, 2020 Arch Oncology, Inc., a clinical-stage immuno-oncology company focused on the discovery and development of anti-CD47 antibody therapies, reported that the first patient has been dosed in a new Phase 1/2 clinical trial for AO-176 in relapsed/refractory multiple myeloma (Press release, Arch Oncology, DEC 7, 2020, View Source;utm_medium=rss&utm_campaign=arch-oncology-announces-first-patient-dosed-in-phase-1-2-clinical-trial-of-anti-cd47-antibody-ao-176-in-multiple-myeloma [SID1234572317]). AO-176 is an anti-CD47 antibody with a potential best-in-class profile that works by blocking the "don’t eat me" signal and also by directly killing tumor cells, with preferential binding to tumor versus normal cells. In preclinical myeloma models involving large tumors, AO-176 has demonstrated promising activity as a single agent as well as in combination with standard approved therapies used to treat this disease.

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"We are excited to begin dosing patients in our second clinical trial for AO-176," said Julie Hambleton, M.D., Interim President and Chief Executive Officer of Arch Oncology. "This is an important milestone for AO-176 and for patients as this is the first dedicated trial of an anti-CD47 antibody exclusively in patients with multiple myeloma. In our first clinical trial of AO-176, we saw encouraging anti-tumor activity as a single agent in patients with solid tumors and we are excited to evaluate our therapy for patients with multiple myeloma. With this second clinical trial initiated, we are making progress advancing AO-176 for both solid tumors and hematologic malignancies as we aim to deliver new cancer treatments to broader groups of patients."

Paul Richardson, M.D., Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Co-Principal Investigator for this clinical trial, commented, "Research shows AO-176 has a highly-differentiated mechanism among this promising new class of anti-CD47 agents. We look forward to evaluating AO-176 as a monotherapy and in combination with standard therapies for patients with relapsed and refractory multiple myeloma. Patients who have progressed despite multiple lines of prior treatment urgently need new treatment options, and we are eager to assess the safety and preliminary efficacy profile of this exciting novel agent."

This open-label, multi-center, dose-escalation Phase 1/2 trial is evaluating the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary efficacy of AO-176 in patients with relapsed/refractory multiple myeloma. Up to 100 patients whose disease has progressed following at least three prior lines of treatment will be enrolled. In Phase 1, patients enrolled in up to four dose-escalation cohorts will receive AO-176 monotherapy. Next, patients will receive AO-176 in combination with dexamethasone and bortezomib. Then, in Phase 2, patients will receive a recommended dose of AO-176 in combination with dexamethasone and bortezomib to evaluate the safety and preliminary efficacy of this combination.

Parameswaran Hari, MD, MRCP, MS, Chief of the Division of Hematology and Oncology in the Department of Medicine and Professor at Medical College of Wisconsin and Principal Investigator for this clinical trial, added, "We are pleased to dose the first patient in this new multiple myeloma clinical trial. As we treat patients with multiple myeloma, an incurable disease for many patients, we look forward to evaluating AO-176 as a potential new treatment option for patients living with this disease. Given the mechanism and profile of AO-176, we envision additional future combinations with AO-176 to evaluate as future treatments for patients."

Recent Preclinical Data Presentations on AO-176 in Multiple Myeloma

Event: ASH (Free ASH Whitepaper) Annual Meeting & Exposition 2020

Date: December 5, 2020 7:00 am – 3:30 pm PT
Abstract Title: Pre-clinical Combination of AO-176, a Highly Differentiated Clinical Stage CD47 Antibody, with Either Azacitidine or Venetoclax Significantly Enhances DAMP Induction and Phagocytosis of Acute Myeloid Leukemia

Date: December 6, 2020 7:00 am – 3:30 pm PT
Abstract Title: AO-176, a Highly Differentiated Clinical Stage Anti-CD47 Antibody, Exerts Potent Anti-Tumor Activity in Preclinical Models of Multiple Myeloma as a Single Agent and in Combination With Approved Therapeutics

About AO-176

AO-176 is a humanized anti-CD47 IgG2 antibody with a potential best-in-class profile. AO-176 is highly differentiated, with the potential to improve upon the safety and efficacy profile relative to other agents in this class of innate checkpoint inhibitors. AO-176 works by blocking the "don’t eat me" signal, the standard mechanism of anti-CD47 antibodies. Beyond blocking this signal, AO-176 has additional mechanisms, including directly killing tumor cells and inducing DAMPs (Damage Associated Molecular Patterns), resulting in Immunogenic Cell Death. Importantly, AO-176 binds preferentially to tumor cells, instead of to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Publications and presentations on AO-176 can be found at View Source

AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and multiple myeloma, both as monotherapy and in combination with standard therapies. In a Phase 1 trial in solid tumors, AO-176 demonstrated encouraging safety and evidence of anti-tumor activity when administered as a single agent. Additional information about these trials may be found at www.clinicaltrials.gov using the trial identification number NCT03834948 (solid tumors) or NCT04445701 (multiple myeloma).