Study, in patients with solid tumors focusing on gynecological malignant tumors such as ovarian, endometrial, and cervical, nearing completion with three remaining subjects to be enrolled
27% Objective Response Rate (ORR)
33% Clinical Benefit Rate (CBR) with a median Progression Free Survival (PFS) of 57 weeks
Chemotherapy-free immunomodulatory regimen well-tolerated with no documented serious immune-related adverse events
CRANFORD, N.J., Nov. 11, 2024 /PRNewswire/ -- Citius Pharmaceuticals, Inc. ("Citius Pharma" or the "Company") (Nasdaq: CTXR) and Citius Oncology, Inc. ("Citius Oncology") (Nasdaq: CTOR), today announced promising preliminary results from an ongoing investigator-initiated Phase I clinical trial evaluating the safety and efficacy of a combined regimen of pembrolizumab and LYMPHIR™ (denileukin diftitox-cxdl or E7777) in patients with recurrent solid tumors. The data was summarized in a poster presentation titled "T-regulatory Cell Depletion with E7777 (denileukin diftitox-xcdl) Combined with Pembrolizumab in patients with recurrent solid tumors: Phase I trial" presented at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting held November 8-10, 2024 (Abstract 614).
The trial is being conducted by Haider Mahdi, M.D., Assistant Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, at the University of Pittsburgh. The study aims to identify an optimal dose for future trials and explore the impact of a treatment regimen combining pembrolizumab and LYMPHIR on the tumor immune microenvironment.
"We have seen promising results in patients with heavily pre-treated recurrent or metastatic gynecologic tumors and will enroll three additional patients before completing the Phase I portion of this study," said Mahdi. "We will further investigate in patients with gynecologic tumors and those with other solid tumor histologies. We want to explore the impact of this therapy on Tregs, host immune-effector cells and the tumor microenvironment."
"The preliminary results from this Phase I trial of patients with recurrent gynecological cancers are highly encouraging. This novel chemo-free immunomodulatory combination regimen has been well tolerated, including at the highest dosage. This efficacy data strongly suggests that LYMPHIR may have the ability to improve and prolong the anti-tumor activity of immune checkpoint inhibitors. To date, this unique regimen has not been associated with significant immune-related adverse events. Moreover, of the 15 evaluable patients, one third experienced a clinical benefit with a median of more than 12 months of progression free survival," stated Dr. Myron Czuczman, Chief Medical Officer of Citius Pharmaceuticals and Citius Oncology.
"There is reason to be optimistic about the potential of LYMPHIR to boost a patient's response to pembrolizumab by temporarily depleting Tregs that modulate the tumor microenvironment, without triggering an autoimmune response from the patient's body. We believe the positive signals from this data support expanding the research in a Phase II study to further evaluate the combination's benefits across a broader range of solid tumor types," he added.
PD-1 inhibitors such as pembrolizumab are a type of immune checkpoint inhibitor that works by blocking the PD-1 protein on T cells, enabling the immune system to recognize and attack cancer cells. Pembrolizumab, developed by Merck and sold under the brand name KEYTRUDA®, is the leading PD-1 inhibitor and world's most prescribed drug, generating $25 billion in sales in 2023.
Preliminary Results
The results of this chemotherapy-free regimen combining two immuno-modulator agents, pembrolizumab (anti-PD-1) and LYMPHIR (transient Treg depletion) demonstrated:
- An overall response rate (ORR) of 27% (4/15) and a clinical benefit rate of 33% (5/15) among evaluable patients; and,
- Median progression-free survival (PFS) for patients achieving clinical benefit of 57 weeks, with a range of 30 to 96 weeks.
- Notably, two of the four patients who achieved partial remission had received prior checkpoint inhibitors (i.e. anti-PD-1 therapy). This highlights the therapeutic potential of LYMPHIR plus immune checkpoint inhibitors to be effective in patients who fail prior anti-PD-1/L1 therapy.
The trial enrolled 21 patients with recurrent or metastatic solid tumors. Among the evaluable participants, four patients achieved a partial response, and one patient demonstrated durable stable disease lasting over six months. The combination regimen was generally well tolerated, with most adverse events related to the patients' underlying disease. Importantly, no significant immune-related adverse events were observed, and only one case of dose-limiting toxicity (capillary leak syndrome) was reported at the highest dose level (12 mcg/kg).
Table 1: Efficacy Data
Value | |
Patients Enrolled | 21 |
Patients Evaluable for Response | 15 |
Partial Responses (PR) | 4 (27 %) |
Stable Disease (≥ 6 months) | 1 |
Clinical Benefit Rate (CBR) | 33% (PR + SD ≥ 6 months) |
Median Progression-Free Survival (PFS) | 57 weeks (range: 30-96 weeks) |
Table 2: Safety Data
Value | |
Dose-Limiting Toxicities (DLTs) | 1 (Capillary Leak Syndrome at 12 mcg/kg) |
Immune-Related Adverse Events (irAEs) | None documented (≥ Grade 3) |
Adverse Events (Grade ≥ 3) | Most related to underlying disease |
Trial Design
The Phase I trial is an open-label study designed to evaluate the safety and preliminary efficacy of pembrolizumab, an anti PD-1 inhibitor, in combination with LYMPHIR in patients with recurrent or metastatic solid tumors. The trial employs a dose-escalation approach, with LYMPHIR administered in four dose levels (3, 6, 9, and 12 mcg/kg) in combination with pembrolizumab (200 mg) on a 21-day cycle for eight cycles. Following the combination regimen, patients receive pembrolizumab monotherapy as maintenance therapy. The study utilizes the Time-to-Event Continual Reassessment Method (TITE-CRM) to assess dose-limiting toxicities (DLTs) and determine the recommended Phase II dose (RP2D).
Key inclusion criteria include measurable disease, ECOG performance status of 0-1, and adequate organ function. Patients with recurrent or metastatic solid tumors who have received at least one prior line of therapy were eligible for enrollment.
The trial enrolled patients with a variety of recurrent or metastatic solid tumors, including ovarian, endometrial, and cervical cancers.
- Ovarian Cancer: Ovarian cancer is the eighth most common cancer in women worldwide, with an estimated 324,000 new cases diagnosed annually. In the United States, approximately 240,000 women are currently living with ovarian cancer.
- Endometrial Cancer: Worldwide, approximately 420,000 new cases are diagnosed each year. Endometrial cancer is the most common gynecologic cancer in the United States, with approximately 66,000 new cases diagnosed each year. It is estimated that over 600,000 women in the U.S. are living with endometrial cancer.
- Cervical Cancer: Cervical cancer remains a major health concern globally, with around 660,000 new cases annually. It is the fourth most common cancer among women. In the United States, approximately 11,500 women are diagnosed each year.
About LYMPHIR™ (denileukin diftitox-cxdl)
LYMPHIR is a targeted immune therapy for relapsed or refractory cutaneous T-cell lymphoma (CTCL) indicated for use in Stage I-III disease after at least one prior systemic therapy. It is a recombinant fusion protein that combines the IL-2 receptor binding domain with diphtheria toxin fragments. The agent specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. After uptake into the cell, the DT fragment is cleaved and the free DT fragments inhibit protein synthesis, resulting in cell death. Denileukin diftitox-cxdl demonstrated the ability to deplete immunosuppressive regulatory T lymphocytes (Tregs) and antitumor activity through a direct cytocidal action on IL-2R-expressing tumors.
In 2021, denileukin diftitox received regulatory approval in Japan for the treatment of CTCL and PTCL. Subsequently, in 2021, Citius acquired an exclusive license with rights to develop and commercialize LYMPHIR in all markets except for Japan and certain parts of Asia. LYMPHIR was approved by the FDA in August 2024.
INDICATION
LYMPHIR is an IL2-receptor-directed cytotoxin indicated for the treatment of adult patients with r/r Stage I-III cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: CAPILLARY LEAK SYNDROME
Capillary leak syndrome (CLS), including life-threatening or fatal reactions, can occur in patients receiving LYMPHIR. Monitor patients for signs and symptoms of CLS during treatment. Withhold LYMPHIR until CLS resolves, or permanently discontinue based on severity.
WARNINGS AND PRECAUTIONS
Capillary Leak Syndrome
LYMPHIR can cause capillary leak syndrome (CLS), including life-threatening or fatal reactions. CLS was defined in the clinical trials as the occurrence of at least 2 of the following symptoms at any time during LYMPHIR therapy: hypotension, edema, and serum albumin