On December 7, 2019 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines seeking to improve the survival and quality of life of cancer patients, reported the presentation of key abstracts highlighting COPIKTRA (duvelisib) data at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting taking place December 7-10, 2019, in Orlando (Press release, Verastem, DEC 7, 2019, View Source [SID1234552048]).
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"Given the aggressive nature of peripheral T-cell lymphoma (PTCL) and the lack of effective therapeutic options for these patients, we are pleased to present data from the dose optimization phase of our PRIMO trial that demonstrated a 62% overall response rate (ORR), as assessed by independent central review, with a manageable safety profile consistent with previous clinical trials. The results of the trial also identified the optimal dosing regimen for future clinical study," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "The expansion phase of this registration-directed study is well underway. Upon completion, we plan to build upon our existing Fast Track Designation and Orphan Drug Designation and submit a regulatory package to the U.S. FDA with the goal of broadening the use of COPIKTRA to include treatment of PTCL."
Results from the Dose Optimization Portion of the Phase 2 PRIMO Study in Relapsed or Refractory PTCL
The PRIMO study is a multi-center, open-label, registration-directed Phase 2 study evaluating duvelisib in patients with relapsed or refractory PTCL that is expected to enroll approximately 120 patients. In the dose optimization portion of the study, patients were randomized to receive duvelisib 25mg twice daily with an option for dose escalation (cohort 1) or duvelisib 75mg twice daily continuously (cohort 2) until disease progression or unacceptable toxicity. The primary endpoint of the study was investigator-assessed overall response rate (ORR), and secondary endpoints included duration of response (DOR) and safety.
A total of 33 patients (cohort 1, n=20; cohort 2, n=13) were treated in the dose optimization phase. Investigator-assessed ORRs were 35% in cohort 1 and 54% in cohort 2, with complete response (CR) rates of 25% and 31% in cohort 1 and cohort 2, respectively. ORR, as assessed by blinded independent central review was 40% in cohort 1 and 62% in cohort 2. Thirteen of 20 patients in cohort 1 and all patients in cohort 2 were able to complete one cycle of therapy. Seven patients in cohort 1 discontinued therapy early due to disease progression and/or toxicity. Most responses were observed at the end of cycle 1 (cycle=28 days). At a median follow-up of 21.4 weeks, the majority of responders were still in response at the time of their last assessment. The most common (≥4 patients) Grade ≥3 adverse events (AEs) in all patients receiving duvelisib were neutropenia, thrombocytopenia, diarrhea, rash/maculopapular, lymphocytopenia, pneumonia and sepsis. Serious AEs occurring in ≥2 patients were colitis, diarrhea, abdominal pain, pyrexia, sepsis, pneumonia, hyponatremia, rash/maculopapular, dyspnea, and respiratory failure.
Based on these efficacy and safety data, the investigators have elected to investigate duvelisib starting at 75mg twice daily for two cycles, followed by 25mg twice daily, during the dose expansion portion of the study which is currently ongoing.
"In the dose optimization portion of the PRIMO study we observed encouraging results, including complete and durable responses at both dose levels," said Steven Horwitz, MD, Memorial Sloan Kettering Cancer Center, and principal investigator of Phase 2 PRIMO study. "We also identified a strategy for the expansion phase dosing regimen starting with 75mg twice daily for two cycles to achieve more a reliable initial tumor response, followed by 25mg twice daily to try to maintain longer-term disease control by mitigating the potential for later onset toxicity in these patients with relapsed or refractory disease."
Results from Phase 1 Study Investigating Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL/SLL
Another key presentation at the meeting highlights new data from an investigator-sponsored Phase 1 study exploring duvelisib in combination with venetoclax in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Duvelisib plus venetoclax demonstrated promising clinical activity, a manageable tolerability profile, and a recommended Phase 2 dose (RP2D) of 400mg of venetoclax was determined for this regimen.
In the study, 12 patients were enrolled and received oral duvelisib and oral venetoclax. The primary endpoints of the study are dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and identification of the RP2D. Secondary endpoints include pharmacokinetics and preliminary efficacy.
Among the 12 evaluable patients, 11 achieved a response for an ORR of 92%, including four (33%) CRs and seven (58%) partial responses. Four patients had undetectable minimum residual disease (uMRD) in the peripheral blood and bone marrow, including two patients with a CR. The most common Grade 1 and 2 AEs were fatigue (92%), hyperglycemia (83%), anemia (67%), and thrombocytopenia (67%). The most common Grade ≥3 AEs were neutropenia (84%), hypocalcemia (50%), and hypophosphatemia (25%). No DLTs were observed, and the RP2D of venetoclax was identified as 400mg once daily when given with standard dose duvelisib 25mg twice daily. This study is now in a Phase 2 portion in CLL/SLL and Richter’s Syndrome and is currently accruing new patients.
"Duvelisib plus venetoclax is a promising combination for further study, as we have found early signals of robust activity along with a manageable tolerability profile," said Matthew S. Davids, MD, Associate Director, Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute, and Principal Investigator for the trial. "We are now actively accruing patients in the Phase 2 portion of the study to evaluate the efficacy of this combination in patients with CLL/SLL, with a separate cohort exploring the activity of this regimen for patients with Richter’s Syndrome, a particularly hard to treat population."
Other poster presentations at the meeting include: an analysis of cytogenetic and molecular markers associated with improved outcomes in the patients who had received 1 prior therapy in the Phase 3 DUO study and a description of the soon to be initiated TEMPO study investigating an intermittent dosing regimen of duvelisib in patients with indolent non-Hodgkin lymphoma.
The data from these studies continues to support the future potential expansion of duvelisib across multiple indications and lines of therapy.
Details for the ASH (Free ASH Whitepaper) 2019 presentations are as follows:
Poster Presentations
Title: Dose Optimization of Duvelisib in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma from the Phase 2 PRIMO Trial: Selection of Regimen for the Dose-Expansion Phase
Lead author: Steven Horwitz, Memorial Sloan Kettering Cancer Center
Poster #: 1567
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma – Clinical Studies: Poster I
Date and Time: Saturday, December 7, 2019; 5:30-7:30PM ET
Location: Orange County Convention Center, Hall B
Title: A Phase I Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL / SLL
Lead author: Jennifer Crombie, Dana-Farber Cancer Institute
Poster #: 1763
Session: 642. CLL: Therapy, excluding Transplantation: Poster I
Date and Time: Saturday, December 7, 2019; 5:30-7:30 PM ET
Location: Orange County Convention Center, Hall B
Title: The Dual PI3K-δ/γ Inhibitor Duvelisib in Combination with the Bcl-2 Inhibitor Venetoclax Shows Promising Responses in Richter Syndrome-PDX Models
Lead author: Andrea Iannello, University of Turin
Poster #: 2862
Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster II
Date and Time: Sunday, December 8, 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B
Title: Cytogenetic and Molecular Marker Associations to Outcomes with Duvelisib and Ofatumumab Treatment in Patients with Relapsed or Refractory CLL/SLL in the DUO Trial
Lead author: Jennifer Brown, Dana-Farber Cancer Institute
Poster #: 4312
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
Publication Only Presentations
Title: Trial in Progress (TiP): A Phase 2, Randomized, Open-Label, 2-Arm Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) (TEMPO)
Lead author: Reem Karmali, Lurie Cancer Center, Northwestern University
Session: 623. Mantle cell, follicular, and other indolent B Cell Lymphoma – Clinical studies
PDF copies of these poster presentations will be available here after the meeting.
COPIKTRA is indicated in the US for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies and in relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. Accelerated approved in FL was based on overall response rate and continued approval may be contingent upon confirmatory trials.
SELECT IMPORTANT SAFETY INFORMATION
This does not include all information needed to use COPIKTRA (duvelisib) safely and effectively. See full Prescribing Information.
WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS
See full Prescribing Information for complete boxed warning
Fatal and/or serious infections occurred in 31% (4% fatal) of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.
Fatal and/or serious diarrhea or colitis occurred in 18% (<1% fatal) of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.
Fatal and/or serious cutaneous reactions occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Withhold COPIKTRA.
Fatal and/or serious pneumonitis occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS
Hepatotoxicity: Monitor hepatic function.
Neutropenia: Monitor blood counts.
Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS
The most common adverse reactions (≥20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.
To report Adverse Reactions, contact FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch and Verastem Oncology at 1-877-7RXVSTM (1-877-779-8786).
DRUG INTERACTIONS
CYP3A inducers: Avoid co-administration with strong CYP3A inducers.
CYP3A inhibitors: Monitor for COPIKTRA toxicities when co-administered with strong or moderate CYP3A inhibitors. Reduce COPIKTRA dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors.
CYP3A substrates: Monitor for signs of toxicities when co-administering COPIKTRA with sensitive CYP3A substrates.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed.
Please see full Prescribing Information, including Boxed Warning.
About COPIKTRA (duvelisib)
COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status and Orphan Drug Designation, and is being investigated in combination with other agents through investigator-sponsored studies.4 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.