Oncotelic Therapeutics Receives FDA Clearance for Phase 2 Clinical Trial of OT-101/Pembroluzimab Combination for Mesothelioma (M201)

Oncotelic Therapeutics, Inc. recently announced the clearance of the Phase 2 clinical trial protocol for mesothelioma after filing the protocol to the US FDA. Oncotelic is initiating a Phase 2 Investigator Initiated Study (IIS) clinical trial in patients with metastatic plural mesothelioma (MPM) in collaboration with Merck who is supplying pembrolizumab for the study.

The trial is titled M201: Phase 2 Trial of TGF-β Inhibition (OT-101) with Anti-PD-1 (pembrolizumab) in Patients with Malignant Pleural Mesothelioma (MPM) Failing to Achieve or Maintain Response to Checkpoint Inhibition. The trial is expected to enroll up to 63 patients across multiple centers in the US, including the center with the Principal Investigator – Melina Marmarelis, MD MSCE, Assistant Professor, Perelman School of Medicine, University of Pennsylvania, Medical Director of the University of Pennsylvania Pleural and Mesothelioma Center.

“This study encompasses a broad clinical strategy, which includes a robust and rigorous assessment of changes within the tumor microenvironment of various indications relative to pre and post therapy including the measurement of nearly 800 genes, spatial distribution of immune effector cells, expression of cytokines, phenotypic and functional changes, immunohistochemistry, and deep sequencing in the hopes of better understanding the etiology and progression of malignancies and ultimately clinical benefit,” said Dr. Anthony E. Maida, Chief Clinical Officer – Translational Medicine, Oncotelic Therapeutics, Inc.

This is a Phase 2, open label, non-randomized, single arm Simon’s two-stage study in subjects with malignant pleural mesothelioma failing to achieve or maintain response to checkpoint inhibition. Before the efficacy assessment portion, the study will first embark a run-in dose-escalation phase to evaluate safety and tolerability of various dose of OT-101 in combination of pembrolizumab, and to determine a recommended Phase 2 dose (RP2D) of 4 days continuous i.v. infusion for every 2 weeks regimen. Subjects received the RP2D in the run-in dose-escalation phase will be part of the first stage of the Simon’s two-stage design for effectiveness evaluation.

A maximum of 63 subjects will be treated. Among them, a maximum of 30 subjects will be treated in the run-in dose-escalation phase to determine the MTD and RP2D. Thirty-nine subjects are required for the Simon’s two-stage assessment of efficacy: 19 subjects in the first stage, and 20 in the second stage. Subjects of the RP2D cohort in the run-in dose-escalation phase will be included in the first stage of the Simon’s two-stage assessment.

Primary Objective:

To determine whether the administration of TGF-β inhibitor (OT-101) in combination with pembrolizumab can provide improved tumor response (ORR) in MPM subjects that fail to achieve or maintain a response with anti-PD-1/PD-L1-based regimens.

Secondary Objectives:

1) To determine whether ORR induced by TGF-β inhibition combined with PD-1 blockade will result in an improved duration of response (DOR) and 6-month and 12-month Overall Survival (OS) and progression-free survival (PFS) as compared to current data with single agent pembrolizumab.

2) To evaluate the safety and tolerability of the administration of OT-101, in combination with pembrolizumab in patients with mesothelioma.

Exploratory Objective:

1) To determine whether TGF-β inhibition combined with PD-1 blockade will increase T cell infiltration, clonality in some tumors; and, the increased T cell infiltration, clonality (CD4, CD8 and Tregs) and IFN- λ signatures correlate with the reduced TBRS.

2) To determine if pretreatment TBRS signature is predictive of improved efficacy per ORR, DOR, and 6-month and 12-month overall survival OS, and progression free survival PFS.

Oncotelic (f/k/a Mateon Therapeutics, Inc.), was formed in the State of New York in 1988 as OXiGENE, Inc., was reincorporated in the State of Delaware in 1992, and changed its name to Mateon Therapeutics, Inc. in 2016, and Oncotelic Therapeutics, Inc. in November 2020. Oncotelic is seeking to leverage its deep expertise in oncology drug development to improve treatment outcomes and survival of cancer patients with a special emphasis on rare pediatric cancers. Oncotelic has rare pediatric designation for DIPG (OT-101) through its 45% joint venture with Dragon Overseas Capital Limited (Dragon) and GMP Biotechnology Limited (GMP Bio), melanoma (CA4P), and AML (OXi 4503). Oncotelic also acquired PointR Data Inc. in November 2019.

Oncotelic acquired AL-101, during the 4th quarter of 2021, for the intranasal delivery of apomorphine. We intend to develop AL-101 for the treatment of Parkinson Disease (PD). Over 60,000 new patients are being diagnosed with PD in the US and currently there are over 1 million patients in the US and expected to increase to over 1.2 million by 2030. In addition, approximately 10 million suffer from this disease globally. https://www.parkinson.org/Understanding-Parkinsons/Statistics.

AL-101 is also being developed for Erectile Dysfunction (“ED”). ED is the most prevalent male sexual disorder globally. The percentages of men affected by ED are as follows: 14.3-70% of men aged ≥60 years, 6.7-48% of men aged ≥70 years, and 38% of men aged ≥80 years (Geerkens MJM et al. (2019). Eur Urol Focus. pii: S2405-4569(19)30079-3). However, with the increasing administration of PDE5 inhibitors in clinical practice, it was found that approximately 30-35% of ED patients are treatment failures (McMahon CN et al. (2006). BMJ, 332: 589-92). AL-101 is designed to target treatment failure ED patients who do not respond to PDE5 inhibitors. Through similar mechanism of action, AL-101 is being developed for Female Sexual Dysfunction (FSD). Female sexual dysfunction is a prevalent problem, afflicting approximately 40% of women and there are few treatment options. FSD is more typical as women age and is a progressive and widespread condition. (Allahdadi, KJ et al. (2009) Cardiovascular & hematological agents in medicinal chemistry, 7(4), 260–269). There is no available drug for the treatment of FSD. In June 2019, the US FDA approved Vyleesi (bremelanotide) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. This is the only available drug treatment. Vyleesi has essentially replaced the only other drug for HSDD – however, it has a long list of drug-drug interactions, including commonly used antidepressants, such as fluoxetine and sertraline. In addition, it has a black box warning regarding its use with alcohol, a combination that has been associated with hypotension and syncopal episodes. Therefore, there is an urgent need for effective therapy against FSD and HSDD.

Oncotelic jointly owns OT-101 with its joint venture partners Dragon and GMP Bio. OT-101 has completed seven clinical trials including one phase 2 trial in COVID and two Phase 2 trials in brain cancer and against pancreatic cancer. It has pediatric designation for a rare form of pediatric brain cancer known as DIPG. There are about 200-300 new cases of DIPG every year in the US. DIPG most often occurs in children aged 5-10 years old. Treatment options are limited with surgery being contraindicated. Most children do not survive more than 2 years after diagnosis. Currently, the main treatment for DIPG is radiation therapy. Although radiation temporarily improves symptoms in most patients, it is not a cure. Palliative care or quality of life services help patients and families manage pain and other symptoms, promote quality of life, and making difficult decisions including treatment choices and end of life care.

When COVID-19 emerged in China, Oncoteli,c and Golden Mountain Partners entered into a research and services agreement in February 2020 to develop and test COVID-19 antisense therapeutics. In March 2020, Oncotelic reported the anti-viral activity of OT-101. The anti-viral activity of OT-101, in an in vitro antiviral testing performed by an independent laboratory, OT-101 has a 50% effective concentration (EC50) of 7.6 µg/mL and is not toxic at the highest dose of 1000 µg/mL giving a safety index (SI) value of >130, which is considered highly active and on par or superior to Remdesivir – a Gilead drug. Unlike Remdesivir, OT-101 targets not only the virus replication but also the virus induced pneumonia and fibrosis. Our Phase 2 trial was completed for OT-101 in South America. This was a randomized, double-blind, placebo-controlled Phase 2 study intended to evaluate the safety and efficacy of OT-101 in adult patients hospitalized with positive SARS-CoV-2 and pneumonia. As reported in November 2021, the top line data was positive for safety and efficacy. For more information, visit www.oncotelic.com