Zandelisib plus rituximab (Rituxan) is being evaluated as a potentially chemotherapy-free treatment strategy vs standard chemoimmunotherapy in patients with indolent non-Hodgkin lymphoma (iNHL) in first relapse in the ongoing, phase 3 COASTAL trial (NCT04745832).

Zandelisib is a potent, selective, and structurally unique, oral PI3Kδ inhibitor under development for the treatment of patients with B-cell malignancies.

A chemotherapy-sparing regimen may be of benefit to patients with iNHL whose disease relapsed after receiving chemoimmunotherapy in the frontline setting.

On March 31, 2020, the FDA granted zandelisib a fast track designation for the treatment of adult patients with relapsed/refractory follicular lymphoma who have received at least 2 prior systemic therapies.

In an ongoing phase 1b single-arm, dose-escalation/-expansion study (NCT02914938), the agent elicited a response rate ranging from 83% to 89% and a median duration of response that was not reached in an intermittent schedule as monotherapy and in combination with rituximab in patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, and B-cell NHL.

“Durable responses were achieved regardless of the number of prior chemotherapy lines or tumor bulk,” said lead study author Wojciech Jurczak, MD, PhD, of the Maria Sklodowska-Curie National Research Institute of Oncology in Krakow, Poland, in a virtual presentation of the study schema during the 2021 ASCO Annual Meeting.

Additionally, less than 10% of patients who were treated with the agent experienced grade 3 or greater immune-mediated adverse effects of special interest.

The COASTAL study is a multicenter, open-label, randomized, controlled, phase 3 trial investigating the safety and efficacy of zandelisib plus rituximab vs standard chemoimmunotherapy in patients with iNHL.

To be eligible for enrollment, patients must have relapsed/refractory follicular lymphoma or marginal zone lymphoma (MZL) and received at least 1 prior line of therapy, including an anti-CD20 antibody in combination with chemotherapy or lenalidomide (Revlimid); at least 1 bi-dimensionally measured lesion greater than 1.5 cm; adequate bone marrow and renal and hepatic function; and an ECOG performance status score of 0 or 1.

Patients will be excluded from enrollment if they have a histologically confirmed diagnosis of grade 3b follicular lymphoma or transformed disease; received 2 prior chemoimmunotherapy regimens; received prior PI3K inhibitor therapy; have ongoing or a history of drug-induced pneumonitis; known lymphomatous involvement of the central nervous system, or are seropositive for or have an active viral infection.

In the study, patients will be randomized 1:1 to receive zandelisib plus rituximab or physician’s choice of chemoimmunotherapy of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) or bendamustine plus rituximab. Patients will be stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy.

Patients will receive zandelisib with rituximab for the first 6 cycles followed by 20 cycles of zandelisib alone. Rituximab will be given weekly in the first cycle followed by monthly administration for the remaining 5 cycles. Chemoimmunotherapy will be administered for a total of 6 cycles.

Zandelisib will be administered in a 28-day cycle consisting of daily dosing for the first 2 cycles followed by intermittent schedule dosing on days 1 through 7 of each of the 24, 28-day cycles thereafter for a duration of 2 years.

Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter.

The primary end point is progression-free survival. Key secondary end points include objective response rate, complete response rate, overall survival, patient-reported outcomes, and safety.

The trial will enroll approximately 534 patients across 200 sites and 25 countries globally and will begin enrollment in mid-2021.

The open-label, phase 2 TIDAL study (NCT03768505) is also ongoing, which is evaluating zandelisib as third- or later-line therapy in patients with relapsed/refractory follicular lymphoma and MZL.

Pending the results of the TIDAL trial, Mei Pharma, the developer of the agent, is planning submissions with the FDA to support accelerated approval marketing applications.

The results of the COASTAL trial are intended to support full marketing applications in the United States and globally in patients with relapsed/refractory follicular lymphoma and MZL who have received at least 1 prior line of treatment. COASTAL is also intended to serve as the confirmatory trial for the potential FDA accelerated approval of zandelisib.

Jurczak W, Zinzani PL, Cunningham D, et al. Coastal: a phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL). 

. 2021;39(suppl 15):TPS7573. doi:10.1200/JCO.2021.39.15_suppl.TPS7573

MEI Pharma announces fast track designation granted by U.S. FDA for ME-401 for the treatment of adult patients with relapsed or refractory follicular lymphoma. News release. Mei Pharma. March 31, 2020. Accessed August 12, 2021. https://bit.ly/3ayo71X.

Zelenetz AD, Reddy N, Jagadeesh D, et al. Tolerability and durable responses of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies. 

. 2020;38(suppl 15):8016. doi:10.1200/JCO.2021.38.15_suppl.8016

Zandelisib (ME-401). Mei Pharma. Accessed August 11, 2021. 

https://www.meipharma.com/pipeline/zandelisib

Articles

Zandelisib plus rituximab is being evaluated as a potentially chemotherapy-free treatment strategy vs standard chemoimmunotherapy in patients with indolent non-Hodgkin lymphoma in first relapse in the ongoing, phase 3 COASTAL trial.

Zandelisib Plus Rituximab Under Study in Indolent Non-Hodgkin Lymphoma

The first participants from the United States have been dosed with LUT014, a novel, topical BRAF inhibitor in a phase 2 trial (NCT04759664) that is evaluating the agent in patients with metastatic colorectal cancer (mCRC) who have developed dose-limiting acneiform lesions following treatment with an EGFR inhibitor, according to a news release from Lutris Pharma, the developer of the agent.

The investigators will continue to recruit and treat patients in Israel, and full unblinded 28-day rolling results will be released in accordance with the trial design, when ready.

“Development of the acneiform rash caused by EGFR inhibitors, including cetuximab [Erbitux], panitumumab [Vectibix] and others, may affect quality of life and consistent dosing, and in the absence of any approved treatments, there is an unmet need for approved topical therapies. Lutris’ phase 1 results in patients with mCRC were promising, with no dose-limiting toxicities and a therapeutic benefit in all patients. As a result, we look forward to participating in the phase 2 trial and to the interim results later this year,” said Mario E. Lacouture, MD, director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center.

LUT014 is a proprietary, first-in-class, small molecule that reverses the effects of EGFR inhibitors on downstream proteins in skin cells, reducing dose-limiting acneiform lesions associated with EGFR inhibitor treatment.

The agent demonstrated “promising” findings, with no dose-limiting toxicities and a clinical benefit in prior findings from the phase 1 trial (NCT03876106) in patients with mCRC.

The ongoing, phase 2, randomized, double-blind, placebo-controlled trial has an expected enrollment of 117 patients across 20 sites, consisting of 15 in the United States, and 5 in Israel.

The 5 sites in the United States include Memorial Sloan Kettering Cancer Center, University of California Los Angeles, Dana-Farber Cancer Institute, University of Tennessee, and The University of Texas MD Anderson Cancer Center.

To be eligible for enrollment, patients must have mCRC with grade 2 EGFR inhibitor–induced acneiform lesions.

“While EGFR inhibitors are critical treatment options, over 80% of mCRC patients experience adverse dermatological [adverse effects], including papulopustular skin rash–also known as acneiform lesions–which reduces their quality of life, and more importantly, may lead to a reduction or discontinuation of treatment. By reversing the inhibitory effect of EGFR inhibitors on downstream proteins in the skin cells, we believe that LUT014 has the potential to become an important addition to therapeutic regimens and can have a tremendous impact for patients who currently have no other treatment options,” said Noa Shelach, PhD, chief executive officer of Lutris Pharma.

Patients will be randomized 1:1:1 to 1 of 2 strengths of LUT014 gel: 0.03% or 0.10%, applied once daily for 4 weeks or placebo, with 4 weeks of follow-up. During an optional open-label extension period, patients randomized to the placebo arm will receive the 0.03% concentration of LUT014.

The primary end point of the study is the proportion of patients in each treatment arm who achieve treatment success, defined as a reduction of at least 1 grade in the severity of the acneiform lesions from baseline to day 28, based on common terminology criteria for adverse events (CTCAE) v5.0 skin and subcutaneous tissue disorders grading scale, or a rise of at least 5 points in the total score for the first 13, skin-specific questions of the functional assessment of cancer therapy epidermal growth factor receptor inhibitor 18 (FACT-EGFRI-18) health-related quality-of-life (HRQOL) questionnaire, from baseline to day 28.

Key secondary end points include the change in the severity of acneiform lesions based on CTCAE grading scale from baseline to days 7, 14, 21, 28, and 55; and the change in the FACT-EGFRI-18 questionnaire total score for the skin-specific questions from baseline to days 7, 14, 21, 28, and 55.

“Dosing of the first United States patients is a significant milestone in the progression of this international, phase 2 trial of LUT014,” said Shelach.

LUT014 is also being evaluated in a phase 1/2 study (NCT04261387) for the treatment of radiation-induced dermatitis in patients with breast cancer.

Lutris Pharma Doses First U.S. Patients in Phase 2 Trial of LUT014 — a Topical Gel for the Reduction of Dose-Limiting Acneiform Lesions — in Metastatic Colorectal Cancer Patients Treated with EGFR Inhibitor Therapy. News release. Lutris Pharma. August 3, 2021. Accessed August 9, 2021. https://prn.to/3lKNENK

The first participants from the United States have been dosed with LUT014, a novel, topical BRAF inhibitor in a phase 2 trial that is evaluating the agent in patients with metastatic colorectal cancer who have developed dose-limiting acneiform lesions following treatment with an EGFR inhibitor.

Topical BRAF Inhibitor, LUT014, Dosed in First US Patients With mCRC for Acneiform Lesions 

The subcutaneously administered peptide cancer vaccine maveropepimut-S (formerly DPX-Survivac) was found to produce promising activity in heavily pretreated patients with recurrent ovarian cancer, according to final topline data from the phase 1/2 DeCidE1 trial (NCT02785250).

At 23.8 months of follow-up, treatment with the vaccine resulted in an overall survival (OS) rate of 44.9%, with a median OS was 19.9 months in this patient population. The approach was also reported to have favorable tolerability.

“The overall results obtained from the DeCidE1 trial are very promising,” Oliver Dorigo, MD, PhD, principal investigator of the study and director of the Gynecologic Oncology Service at Stanford University, stated in a press release. “…These results are particularly encouraging because many subjects in the trail had been heavily pretreated and 57.9% were platinum resistant. We believe that these results support the further clinical study of maveropepimut-S in ovarian cancer.”

Data from an extensive analysis of collected biological samples, which represented key secondary end points of the trial, showed that the vaccine was able to prompt the generation of tumor antigen–specific T cells.

“Importantly, these analyses affirm the molecular and cellular mechanism of maveropepimut-S based therapy,” Jeremy Graff, MD, chief scientific officer of IMV Inc., stated in a press release. “These data will also inform the discussion and design of a phase 2 clinical study to be submitted to the FDA.”

Detailed data from the translational analyses have been submitted for presentation at an upcoming medical meeting, according to IMV Inc.

Maveropepimut-S was designed to generate cancer-targeted T cells in vivo by combining the DPX platform and the cancer antigen survivin.

 When the vaccine is administered via a subcutaneous injection, antigen-presenting cells recruit to the injection site and take up survivin to present to naïve T cells.

From there, the cells migrate to the lymph nodes and present survivin to naïve T cells through the MHCII and the T-cell receptor. This process activates trafficking of activated cytotoxic T cells (CTLs) into the blood. The CTLs then infiltrate the tumor, recognize the survivin on the surface of the cancer cells, and release cytotoxic molecules that can kill the tumor.

Previously, the vaccine has showcased a robust and sustained antigen-specific immune response with the infiltration of the T cells into the tumor following treatment; this has been linked with durable clinical activity that can persist for 2 years or longer.

In the multicenter, randomized, open-label DeCidE1 trial, investigators set out to examine the safety and effectiveness of maveropepimut-S in combination with intermittent low-dose cyclophosphamide (CPA).

A total of 22 patients with recurrent, advanced, platinum-sensitive and -resistant ovarian cancer. To be eligible for enrollment, patients needed to have histologically confirmed, stage IIC to IV epithelial ovarian, fallopian tube, or peritoneal cancer, measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and a life expectancy of at least 6 months.

Patients who were candidates for otherwise curative treatment or who were undergoing concurrent therapy were excluded from the trial. Other exclusion criteria included previous treatment with survivin-based vaccines or immune checkpoint inhibitors, a concurrent second malignancy beyond non-melanoma skin cancer, clinical ascites, a single lesion at least 4 cm, a malignant bowel obstruction, and a history of autoimmune disease that required treatment within the past 2 years, among others.

Participants were administered 2 subcutaneous injections of the vaccine 3 weeks apart and every 8 weeks thereafter, in addition to intermittent low-dose CPA 1-week-on and 1-week-off until the end of treatment. Biopsies of tumor tissue were done before and while on treatment.

The primary end points of the trial included overall response rate, disease control rate, and safety. Key secondary end points comprised cell-mediated immunity, immune cell infiltration in paired biopsy samples, duration of response, time to progression, OS, and biomarker analyses.

“The protein survivin is found in more than 15 types of solid tumor and hematologic cancers. It has been recognized as a promising tumor-associated target because it is overexpressed in a high percentage of tumor types,” according to IMV, Inc. “Survivin plays a critical role in tumor biology…we believe maveropepimut-S’ ability to deliver a sustained flow of T cells that target surviving expressed on cancer cells can lead to more clinically effective antitumor therapies.”

IMV announces final topline results of the DeCidE1 clinical trial in advanced recurrent ovarian cancer. News release. IMV Inc. August 10, 2021. Accessed August 10, 2021. https://bit.ly/37zGVhg

Maveropepimut-S (DPX-Survivac). IMV, Inc. website. Accessed August 10, 2021. https://bit.ly/3fQN8u1

Study of DPX-Survivac therapy in patients with recurrent ovarian cancer. ClinicalTrials.gov. Updated June 18, 2021. Accessed August 10, 2021. https://www.clinicaltrials.gov/ct2/show/NCT02785250

The subcutaneously administered peptide cancer vaccine maveropepimut-S was found to produce promising activity in heavily pretreated patients with recurrent ovarian cancer. 

Pipeline Report: August 2021

Articles

Zandelisib Plus Rituximab Under Study in Indolent Non-Hodgkin Lymphoma

Topical BRAF Inhibitor, LUT014, Dosed in First US Patients With mCRC for Acneiform Lesions