On December 8, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an oncology-focused pharmaceutical company, reported that four posters relating to XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, and eltanexor, its next generation SINE compound, will be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting taking place December 7-10, 2019 in Orlando (Press release, Karyopharm, DEC 8, 2019, View Source [SID1234552038]). The four posters include: updated data from the Kyprolis (carfilzomib) arm of the Phase 1b/2 STOMP study evaluating selinexor in combination with backbone therapies in patients with relapsed or refractory multiple myeloma; new data from the Revlimid (lenalidomide) plus selinexor arm of the STOMP study evaluating this combination in patients with newly diagnosed multiple myeloma; encore data highlighting the previously disclosed comparison of patients in the STORM study, Karyopharm’s Phase 2b study evaluating XPOVIO in patients with heavily pretreated, triple class refractory multiple myeloma, to matched patients from the MAMMOTH study; and new Phase 1/2 data evaluating eltanexor in patients with higher-risk myelodysplastic syndrome (MDS).

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"Efficacy data from our ongoing STOMP study investigating selinexor in combination with standard of care anti-myeloma agents continue to demonstrate a strong rationale for selinexor’s potential expanded role in the future multiple myeloma treatment paradigm," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "The Kyprolis arm of the STOMP study continues to show clear signs of clinical activity, including a complete response rate of 21%, in patients with heavily pretreated Kyprolis-naïve multiple myeloma. Additionally, preliminary data from the Revlimid arm of the Phase 1b/2 STOMP study show early but encouraging clinical activity, including in one patient who achieved a complete response, in patients with multiple myeloma in the front-line setting. And finally, we are pleased to be presenting new data from the eltanexor program showing impressive early activity, including a high rate of complete responses in elderly patients with higher-risk MDS."

Updated Data from Phase 1b/2 STOMP Study Evaluating Selinexor in Combination with Kyprolis and Low-dose Dexamethasone (SKd) in Patient with Relapsed or Refractory Multiple Myeloma

In this arm of the Phase 1b/2 STOMP study, oral selinexor (dosed once-weekly) is being evaluated in combination with Kyprolis (56mg/m2 or 70mg/m2 once weekly) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed refractory multiple myeloma who have received at least two prior therapies, which can include previous treatment with a proteasome inhibitor, one or more immunomodulatory drugs (e.g., Revlimid or Pomalyst) or Darzalex. The median number of prior treatments was four (range: 2-8). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SKd Patients as of 1-Oct-20192
Category N ORR CR VGPR PR
All (Kyprolis-naïve) 14 10 (71%) 3 (21%) 7 (50%) -
Key: ORR=Overall Response Rate (CR+VGPR+PR); CR=Complete Response; VGPR=Very Good Partial Response; PR=Partial Response
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data

All patients had reductions in M-protein from baseline, with 71% of patients experiencing a reduction of ≥90%. Median progression-free survival (PFS) has not yet been reached.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (71%), fatigue (43%), anorexia (36%), vomiting (36%) and weight loss (36%), and were mostly Grade 1 and 2 events. As expected, the most common treatment-related Grade ≥3 AEs were hematologic AEs and included thrombocytopenia (64%), anemia (14%) and leukopenia (14%). The recommended Phase 2 dose (RP2D) was identified as selinexor 80mg and Kyprolis 56mg/m2 and enrollment continues using this regimen.

New Data from Phase 1b/2 STOMP Study Evaluating the All Oral Combination of Selinexor with Revlimid and Low-dose Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

In this all oral arm of the Phase 1b/2 STOMP study in patients with newly diagnosed multiple myeloma, selinexor (60mg once-weekly) is being combined with Revlimid (25mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SRd Patients as of 1-Oct-20192
Category N3 ORR CR VGPR4 PR
All 7 6 (86%) 1 (14%) 4 (57%) 1 (14%)
Key: ORR=Overall Response Rate (CR+VGPR+PR)
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 One patient was not evaluable for response due to withdrawn consent prior to disease follow-up
4 One VGPR was confirmed on Oct 10, 2019 (after data cut); two VGPR are unconfirmed

The data are early and the median PFS was not reached. Among the patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were diarrhea (63%), weight loss (63%), nausea (50%), constipation (38%), fatigue (38%), hypokalemia (38%) and insomnia (38%) and were mostly Grade 1/2. The most common Grade ≥3 AEs were neutropenia (75%), anemia (50%) and thrombocytopenia (25%). Amongst the five patients evaluable for dose limiting toxicities (DLTs), there were no DLTs observed.

Comparison of Overall Survival Rates Between the Phase 2b STORM Study and the MAMMOTH Study

Another key presentation at ASH (Free ASH Whitepaper) 2019 highlights encore data comparing the overall survival (OS) rate from the retrospective MAMMOTH study (Leukemia, 2019). The MAMMOTH study evaluated outcomes of patients with relapsed or refractory multiple myeloma (RRMM) treated at major academic medical centers. This ASH (Free ASH Whitepaper) presentation highlighted results from a comparison of outcomes from patients with RRMM after their disease became refractory to CD38 monoclonal antibodies with a matched cohort of patients from Karyopharm’s Phase 2b STORM study, which served as the basis for the XPOVIO accelerated approval. Thus, patients in STORM who received selinexor and dexamethasone as first line of therapy after their disease became triple class refractory (n=64) were compared with matched patients receiving currently available therapies from the MAMMOTH cohort (n=128), showed an unadjusted hazard ratio (HR) for death of 0.64 (p=0.043), while an adjusted analysis, which takes into consideration differences in baseline characteristics between the two groups, showed a HR of 0.55 (p=0.009). The median OS of patients in STORM was 10.4 months and in MAMMOTH was 6.9 months. These results are consistent with previous presented results of STORM patients versus those from the Flatiron Health Analytics Database (FHAD) from patients with RRMM treated primarily in the community setting (Richardson, et al. ASCO (Free ASCO Whitepaper) 2019). In that analysis, the median OS of patients in STORM was 10.4 months and in FHAD was 5.8 months (p=0.036).

Updated Phase 1/2 Clinical Data for Oral Eltanexor in Elderly Patients with Higher-Risk MDS

This Phase 1/2 study is evaluating the safety, tolerability and anti-tumor activity of single-agent oral eltanexor (10mg or 20mg once-daily for 5 days per week) in elderly patients with higher-risk MDS. All patients were refractory to hypomethylating agents. The following table is a summary of the efficacy results:

Best Responses1 in Eltanexor Patients2
Category N ORR mCR SD
All patients 20 7 (35%) 7 (35%) 5 (25%)
Key: ORR=Overall Response Rate (mCR+HI [not observed]); mCR=Complete Response without marrow recovery; HI=Hematologic Improvement; SD=Stable Disease
1 Responses assessments were made by the treating physician according to the 2006 International Working Group (IWG) Response Criteria for MDS
2 Based on interim unaudited data

Median overall survival was 10.6 months. The most common treatment-related AEs were hematologic, gastrointestinal and constitutional. The most common non-hematologic treatment-related AEs were nausea (45%), decreased appetite (40%), fatigue (35%), diarrhea (35%) and dysgeusia (25%); the vast majority were Grade 1 or 2. The most common Grade ≥3 AEs were anemia (30%), neutropenia (25%), thrombocytopenia (20%) and leukopenia (15%). AEs were dose-dependent and managed with supportive care and dose modification. This Phase 1/2 study remains ongoing.

Other Key Selinexor Presentations

An additional investigator-sponsored study, which will be presented on Monday, December 9, 2019, highlights data from a Phase 1 trial investigating the combination of selinexor and ibrutinib in 33 heavily pretreated, high-risk patients with chronic lymphocytic leukemia or non-Hodgkin lymphoma. This combination was tolerable and demonstrated encouraging efficacy in this high-unmet need patient population warranting additional future clinical investigation.

Details for these ASH (Free ASH Whitepaper) 2019 presentations are as follows:

Poster Presentations – Company-Sponsored Studies

Title: Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma
Presenter: Darrell White, Dalhousie University
Abstract #: 3165
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time: Sunday, December 8, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Title: A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)
Presenter: Cristina Gasparetto, Duke University Medical Center
Abstract #: 3157
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time: Sunday, December 8, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Title: Overall Survival of Triple Class Refractory, Penta-Exposed Multiple Myeloma (MM) Patients Treated with Selinexor Plus Dexamethasone or Conventional Care: A Combined Analysis of the STORM and Mammoth Studies
Presenter: Luciano Costa, University of Alabama at Birmingham
Abstract #: 3125
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time: Date: Sunday, December 8, 2019; 6:00 PM – 8:00 PM ET
Location: Orange County Convention Center, Hall B

Title: Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome
Presenter: Sangmin Lee, Weill Cornell School of Medicine
Abstract #: 2997
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster II
Date and Time: Sunday, December 8, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Poster Presentations – Investigator-Sponsored Studies

Title: Selinexor Combined with Ibrutinib Demonstrates Tolerability and Efficacy in Advanced B-Cell Malignancies: A Phase I Study
Presenter: Deborah Stephens, Huntsman Cancer Institute, University of Utah
Abstract #: 4310
Session: 642. CLL: Therapy, excluding Transplantation: Poster III
Date and Time: Monday, December 9, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

PDF copies of these presentations will be available here following conclusion of the presentations at the meeting.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. In addition to receiving accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), in recurrent gliomas (KING) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia

XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia

XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO.

Nausea/Vomiting

Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.

Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.

Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.

Diarrhea

Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.

Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.

Anorexia/Weight Loss

Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.

Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.

Hyponatremia

XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.

Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Infections

In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.

Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO.

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.

On December 8, 2019 Innate Pharma SA (Euronext Paris: IPH – ISIN: FR0010331421; Nasdaq: IPHA) ("Innate" or the "Company") shared new, reported that long-term data from the pivotal Phase III trial of Lumoxiti (moxetumomab pasudotox-tdfk) at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Orlando, USA, which expands on the efficacy results and affirms the manageable safety profile of the medicine (Press release, Innate Pharma, DEC 8, 2019, View Source [SID1234552026]).

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The final analysis showed that 36 percent (29/80) of the relapsed or refractory hairy cell leukemia patients achieved durable complete response (CR) with Lumoxiti at Day 181 of patients’ respective evaluation, compared to the primary analysis in which 30 percent durable CR rate was reported. In addition, there was a 61 percent probability that patients who achieved a CR would maintain it after five years.

"Lumoxiti is a first-in-class medicine and the only treatment approved in the US for relapsed or refractory hairy cell leukemia in more than twenty years; therefore, it is important for the hematology-oncology community to receive additional analysis of its long-term efficacy," commented Pierre Dodion, MD, Executive Vice President and Chief Medical Officer of Innate Pharma. "We are grateful to the patients and health care professionals who participated in the clinical development of Lumoxiti and we are passionate about continuing to address the unmet need in this rare form of cancer."

The single-arm, multi-center, open-label Phase III ‘1053’ clinical trial assessed the efficacy, safety, immunogenicity and pharmacokinetics of Lumoxiti monotherapy in 80 patients with relapsed or refractory hairy cell leukemia who had received at least two prior therapies, including one purine nucleoside analog. The primary endpoint of durable CR was defined as CR with hematologic remission (HR) for >180 days.

Findings from the final analysis of the Lumoxiti Phase III trial include:

Efficacy measure

Result* (n=80, 95% Confidence Interval)

Durable CR (CR with HR > 180 days)

36.3% (25.8 to 47.8)

CR with HR ≥ 360 days

32.5% (22.4 to 43.9)

CR rate

41.3% (30.4 to 52.8)

CR with MRD-negative status

33.8% (23.6 to 45.2)

Partial Response Rate

33.8%

Hematologic Remission Rate

80.0%

Median duration of CR

62.8 months (0.0+ to 62.8)

Median Progression-Free Survival

41.5 months (range 0.0+ to 71.7)

* BICR = blinded independent central review

"A key treatment goal for patients with relapsed or refractory hairy cell leukemia is to achieve sustained remission, which can be particularly challenging in patients in whom prior therapies have failed. This long-term analysis demonstrates that Lumoxiti achieved a high rate of durable efficacy, while maintaining the benefit risk profile we saw in the primary analysis," said Robert J. Kreitman, MD, Senior Investigator, Head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, and Principal Investigator of the Phase III clinical trial.

The final analysis shows that the risk-benefit profile of Lumoxiti is maintained. There were no new serious adverse events and no change in hemolytic uremic syndrome or capillary leak syndrome. Per the primary analysis on the 1053 study, the most frequent treatment-related adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), headache (33%), and pyrexia (31%). Treatment-related grade 3/4 AEs were reported in 24 patients (30%) and treatment-related serious AEs in 14 patients (18%). Grade 3/4 CLS events occurred in two patients (2.5%) and any grade of HUS occurred in six patients (7.5%). CLS and HUS events were manageable and reversible with appropriate supportive care and monitoring.

Treatment-emergent AEs led to study drug discontinuation in eight patients (10.0%): hemolytic uremic syndrome (HUS), n = 4 (5.0%); capillary leak syndrome (CLS), n = 2 (2.5%); increased blood creatinine, n = 2 (2.5%); renal failure, n =1 (1.3%); vomiting, n =1 (1.3%); and chills, n =1 (1.3%). There were four deaths reported (including the three reported during the primary analysis): two due to disease progression and two due to an AE (1 each of pneumonia and septic shock). No death was considered treatment related.

On December 7, 2019 Cellular Biomedicine Group, Inc Presented the Corporate Presentation (Presentation, Cellular Biomedicine Group, DEC 7, 2019, View Source [SID1234552179]).

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On December 7, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported combination data from two studies and a long-term integrated analysis evaluating the use of IMBRUVICA (ibrutinib) for the treatment of previously untreated patients with CLL or small lymphocytic lymphoma (SLL) (Press release, Janssen Pharmaceuticals, DEC 7, 2019, View Source [SID1234552069]). Results from a 48-month follow-up analysis of the Phase 3 E1912 clinical study reported a statistically significant difference in PFS and OS for IMBRUVICA plus rituximab compared to a standard chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab (FCR). Further, the latest integrated analysis from the Phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115/1116) studies investigating the use of single-agent IMBRUVICA in CLL, reported that at up to six years of follow-up, PFS, OS and response rates improved when IMBRUVICA was used in earlier lines of therapy. During this extended follow-up, IMBRUVICA was tolerated across all lines of therapy with 19 percent of patients discontinuing due to adverse events.

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In addition, results presented from the Phase 2 CAPTIVATE study suggest that patients who received IMBRUVICA plus venetoclax as a time-limited treatment achieved high rates of uMRD in peripheral blood (75 percent of patients) and bone marrow (72 percent of patients).

These new findings from the E1912, RESONATE/RESONATE-2 and CAPTIVATE studies were presented at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"We’re pleased to see follow-up results from the Phase 3 E1912 trial, where the investigational use of IMBRUVICA plus rituximab is shown to extend OS for previously untreated patients with CLL. In addition, with the integrated analysis of the Phase 3 RESONATE and RESONATE-2 studies, IMBRUVICA demonstrated an OS benefit in untreated and relapsed patients with improved outcomes in early lines of therapy," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC. "We are also excited to see the first MRD data from the fixed-duration regimen of IMBRUVICA plus venetoclax in the Phase 2 CAPTIVATE trial, reporting a high rate of undetectable MRD at 15 months both in the peripheral blood and bone marrow."

E1912 extended follow-up of investigational use of IMBRUVICA plus rituximab compared to FCR in patients with CLL/SLL ages 70 or younger (Abstract #33)

Longer-term outcomes data from the Phase 3 E1912 clinical trial – designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health – were also presented. As previously reported in earlier data readouts, the study evaluated 354 previously untreated patients with CLL ages 70 years or younger who were randomly assigned to receive IMBRUVICA and rituximab or six courses of intravenous FCR every 28 days.

At a median follow-up of 48 months, 73 percent of patients in the IMBRUVICA plus rituximab treatment arm remained on IMBRUVICA with median time on treatment of 43 months. PFS benefits were observed for the IMBRUVICA plus rituximab arm as compared to the FCR treatment arm (hazard ratio [HR], 0.39; 95 percent confidence interval [CI], 0.26-0.57; p<0.0001). OS benefit also continued to favor the IMBRUVICA plus rituximab arm (HR, 0.34; 95 percent CI, 0.15-0.79; p=0.009).

Grade 3 and above treatment-related adverse events (AEs) were observed in 70 percent of patients in the IMBRUVICA plus rituximab arm versus 80 percent in the FCR arm (odds ratio [OR], 0.56; 95 percent CI, 0.34-0.90; p=0.013).

The E1912 study served as the basis of the recent supplemental New Drug Application to the U.S. Food and Drug Administration (FDA) to expand the IMBRUVICA label to include the combination with rituximab for the first-line treatment of patients with CLL or SLL. The submission is being reviewed by the FDA under the Real-Time Oncology Review (RTOR) pilot program.

MRD cohort of the Phase 2 CAPTIVATE study on IMBRUVICA plus venetoclax combination in patients with previously untreated CLL/SLL (Abstract #35)
The Phase 2 CAPTIVATE (PCYC-1142) clinical trial evaluated 164 patients younger than 70 years (median age of 58 years) with previously untreated CLL/SLL. Patients received IMBRUVICA monotherapy as lead-in treatment for three cycles, followed by 12 cycles of IMBRUVICA plus venetoclax combination therapy. MRD status was evaluated in peripheral blood (PB) after six, nine, and 12 cycles and in bone marrow (BM) after 12 cycles of IMBRUVICA plus venetoclax.

"The new results from the CAPTIVATE study demonstrated the all-oral regimen of ibrutinib monotherapy followed by combined ibrutinib and venetoclax achieved promising rates of undetectable minimal residual disease, an important indicator of deep response, in previously untreated patients with CLL," said Constantine Tam, M.D., Hematologist and Disease Group Lead, Low Grade Lymphoma and CLL, Peter MacCallum Cancer Centre, Victoria, Australia, and principal study investigator. "We look forward to continuing to explore the efficacy and safety profile of this regimen and its potential to provide a limited-duration option in first-line treatment of CLL."

Results showed undetectable MRD (uMRD) – defined as less than one CLL cell per 10,000 leukocytes (MRD<0.01 percent) by flow cytometry– was achieved at any time after baseline in PB for 75 percent of patients (122 of 163 patients) and in BM for 72 percent (111 of 155 patients). The high rates of uMRD in BM were consistent across high-risk subgroups, including in patients with del(17p); del(17p) or TP53 mutation; del(11q); complex karyotype; and unmutated IGHV status. In patients with uMRD in PB with matched BM samples, 93 percent of patients had uMRD in both PB and BM. With median follow-up of 14.7 months, three patients (2 percent) experienced disease progression.

The most common AEs of any grade (in 20 percent of patients or greater) were diarrhea (31 percent) and arthralgia (22 percent) during treatment with IMBRUVICA alone; and diarrhea (60 percent), neutropenia (40 percent), nausea (34 percent), upper respiratory tract infection (24 percent), and fatigue (20 percent) during treatment with IMBRUVICA plus venetoclax. AEs leading to dose reductions occurred in 20 percent of patients overall. AEs leading to discontinuation were infrequent, occurring in 7 percent of patients overall (IMBRUVICA: 5 percent; venetoclax: 4 percent).

Results from the MRD-guided, randomized treatment discontinuation cohort and fixed-duration cohort of the CAPTIVATE clinical trial are being further evaluated and will be presented at a future medical meeting.

About IMBRUVICA
IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company. IMBRUVICA blocks the BTK protein; the BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.1,2 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.3

IMBRUVICA is the most comprehensively studied molecule in the class with more than 150 ongoing clinical trials and four Phase 3 studies supporting the U.S. label. It is approved in more than 95 countries for at least one indication, and to date, has been used to treat more than 170,000 patients worldwide across approved indications. It was first approved by the U.S. Food and Drug Administration (FDA) in November 2013, and today is indicated in six disease areas, including five hematologic cancers – chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy*; and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.4

* Accelerated approval was granted for MCL and MZL based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

As of early 2019, the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL, and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations by the FDA, and it was one of the first medicines to receive U.S. approval with the Breakthrough Therapy Designation.

For more information, visit www.IMBRUVICA.com.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. 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 hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On December 7, 2019 Cellular Biomedicine Group Inc. (NASDAQ: CBMG) ("CBMG" or the "Company"), a biopharmaceutical firm engaged in the drug development of immunotherapies for cancer and stem cell therapies, reported early data from its ongoing investigator initiated trial ("IIT") at an oral presentation titled "Novel Anti-BCMA CAR-T for Relapsed or Refractory Multiple Myeloma" at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") annual meeting on December 7, 2019 in Orlando, Florida (Press release, Cellular Biomedicine Group, DEC 7, 2019, View Source [SID1234552068]).

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ABSTRACT DETAILS
C-CAR088 is a novel anti-B-cell maturation antigen ("BCMA") chimeric antigen receptor T-cell ("CAR-T") product designed to improve efficacy through increasing the specificity and reducing immunogenicity by fusing a single-chain variable fragment ("scFv") from high-affinity human monoclonal antibody to a CD3ζ/4-1BB signaling domain. It can effectively eradicate BCMA positive tumor cells both in vitro and in vivo.

A Phase 1, dose escalation trial is being conducted in patients with relapsed or refractory Multiple Myeloma ("r/r MM") to assess the safety and efficacy of C-CAR088. As of the end of November the Company has enrolled eleven patients, of which eight were infused with C-CAR088, and five patients were evaluable for clinical response. Three of the five patients were treated with C-CAR088 at the dose of 1.0 x 106 CAR-T cells/kg, and the other two patients treated at 3.0×106 CAR-T cells/kg. All five patients showed clinical improvement as early as two weeks post treatment. By 4 weeks, one patient achieved a complete response ("CR"), three patients reached a very good partial response ("VGPR"), and one patient reached a partial response ("PR") post C-CAR088 infusion. Furthermore, the Company observed that C-CAR088 proliferation & expansion in the peripheral blood correlated with the decrease of tumor burden in all patients. C-CAR088 treatment showed to be well tolerated. There were no dose-limiting toxicities ("DLTs"). Reversible Grade 1 and Grade 2 Cytokine release syndrome ("CRS") were observed in four and one patient respectively.

"The early IIT clinical trial results in patients with relapsed and refractory multiple myeloma for C-CAR088 support preclinical findings that C-CAR088 shows promising efficacy and has a manageable safety profile," stated Dr. Yihong Yao, Chief Scientific Officer of CBMG. Dr. Yao added, "The very early clinical efficacy signal at low and suboptimal dosing is encouraging and needs to be confirmed by the ongoing clinical trial. We will continue to monitor and evaluate the duration of response ("DOR") and to further pursue DOR improvement alternatives."

The complete text of the abstract can be found at View Source
The full presentation can be found on the company’s website.

About Multiple Myeloma
Multiple Myeloma, a cancer derived from plasma cells, accounts for 1% of all cancers and approximately 10% of all hematological malignancies[1]. It is estimated that there are 27,800 new cases of MM diagnosed in China each year. With the acceleration of the aging process in China, it is predicted that MM, with a rapid growth in incidence, will become one of the more significant diseases that affect people’s health in the country[2]. The American Cancer Society estimates that in the United States, approximately 32,110 new cases of MM (18,130 in men and 13,980 in women) will be diagnosed in 2019[3].
[1] Moreau P et al., Annals of Oncology 24 (Supplement 6): vi133–vi137, 2013
[2] Blood Cancer J. 2014 Aug 15;4:e239. doi: 10.1038/bcj.2014.55
[3] View Source