Citius Pharmaceuticals, Inc. and Citius Oncology, Inc. Announce Promising Preliminary Results of an Investigator-Initiated Phase I Clinical Trial of Pembrolizumab (KEYTRUDA®) and LYMPHIR™ in Cancer Patients with Recurrent Solid Tumors
Citius Pharmaceuticals and Citius Oncology announced preliminary results from a Phase I trial evaluating the combination of pembrolizumab (KEYTRUDA®) and LYMPHIR™ in patients with recurrent solid tumors, focusing on gynecological cancers like ovarian, endometrial, and cervical. The trial showed a 27% Objective Response Rate (ORR) and a 33% Clinical Benefit Rate (CBR) with a median Progression-Free Survival (PFS) of 57 weeks. The regimen was well-tolerated, with no serious immune-related adverse events. The study, nearing completion, will enroll three more patients. The results suggest LYMPHIR may enhance the efficacy of immune checkpoint inhibitors like pembrolizumab. The trial's promising outcomes support expanding research into a Phase II study to evaluate the combination's benefits across a broader range of solid tumors.
Citius Pharmaceuticals e Citius Oncology hanno annunciato risultati preliminari da uno studio di Fase I che valuta la combinazione di pembrolizumab (KEYTRUDA®) e LYMPHIR™ in pazienti con tumori solidi recidivanti, con un focus sui tumori ginecologici come quelli ovarici, endometriali e cervicali. Lo studio ha mostrato un tasso di risposta obiettiva (ORR) del 27% e un tasso di beneficio clinico (CBR) del 33%, con una sopravvivenza libera da progressione (PFS) mediana di 57 settimane. Il regime è stato ben tollerato, senza eventi avversi gravi correlati all'immunità. Lo studio, vicino al completamento, arruolerà altri tre pazienti. I risultati suggeriscono che LYMPHIR potrebbe migliorare l'efficacia degli inibitori del checkpoint immunitario come il pembrolizumab. Gli incoraggianti risultati dello studio sostengono l'espansione della ricerca in uno studio di Fase II per valutare i benefici della combinazione su un'ampia gamma di tumori solidi.
Citius Pharmaceuticals y Citius Oncology anunciaron resultados preliminares de un ensayo de Fase I que evalúa la combinación de pembrolizumab (KEYTRUDA®) y LYMPHIR™ en pacientes con tumores sólidos recurrentes, centrándose en cánceres ginecológicos como el ovárico, endometrial y cervical. El ensayo mostró una tasa de respuesta objetiva (ORR) del 27% y una tasa de beneficio clínico (CBR) del 33%, con una mediana de sobrevida libre de progresión (PFS) de 57 semanas. El régimen fue bien tolerado, sin eventos adversos graves relacionados con el sistema inmune. El estudio, que está cerca de completarse, inscribirá a tres pacientes más. Los resultados sugieren que LYMPHIR puede mejorar la eficacia de los inhibidores de puntos de control inmunitario como el pembrolizumab. Los prometedores resultados del ensayo apoyan la expansión de la investigación hacia un estudio de Fase II para evaluar los beneficios de la combinación en un rango más amplio de tumores sólidos.
Citius Pharmaceuticals와 Citius Oncology는 재발성 고형 종양 환자에서 pembrolizumab (KEYTRUDA®)와 LYMPHIR™의 조합을 평가한 1상 시험의 초기 결과를 발표했습니다. 이 시험은 난소암, 자궁내막암 및 자궁경부암과 같은 부인科 암에 중점을 두었습니다. 시험 결과 객관적 반응률 (ORR)은 27%, 임상적 이익률 (CBR)은 33%였으며, 중간 무진행 생존 기간 (PFS)은 57주로 나타났습니다. 이 요법은 잘 견뎌졌으며, 심각한 면역 관련 부작용은 없었습니다. 이 연구는 거의 완료되며 세 명의 환자를 추가로 모집할 계획입니다. 결과는 LYMPHIR이 pembrolizumab과 같은 면역 체크포인트 억제제의 효능을 향상시킬 수 있음을 시사합니다. 이 시험의 유망한 결과는 더 넓은 범위의 고형 종양에 대한 조합의 이점을 평가하기 위한 2상 시험으로의 연구 확장을 지지합니다.
Citius Pharmaceuticals et Citius Oncology ont annoncé des résultats préliminaires d'un essai de Phase I évaluant la combinaison de pembrolizumab (KEYTRUDA®) et de LYMPHIR™ chez des patients atteints de tumeurs solides récidivantes, en mettant l'accent sur les cancers gynécologiques tels que l'ovaire, l'endomètre et le col de l'utérus. L'essai a montré un taux de réponse objective (ORR) de 27 % et un taux de bénéfice clinique (CBR) de 33 %, avec une survie sans progression médiane (PFS) de 57 semaines. Le traitement a été bien toléré, sans événements indésirables graves liés à l'immunité. L'étude, qui est proche de son achèvement, recrute trois autres patients. Les résultats suggèrent que LYMPHIR pourrait améliorer l'efficacité des inhibiteurs de points de contrôle immunitaires comme le pembrolizumab. Les résultats prometteurs de l'essai soutiennent l'expansion de la recherche vers une étude de Phase II pour évaluer les avantages de la combinaison sur une gamme plus large de tumeurs solides.
Citius Pharmaceuticals und Citius Oncology haben vorläufige Ergebnisse einer Phase-I-Studie zur Bewertung der Kombination von Pembrolizumab (KEYTRUDA®) und LYMPHIR™ bei Patienten mit wiederkehrenden soliden Tumoren vorgestellt, wobei der Schwerpunkt auf gynäkologischen Krebserkrankungen wie Eierstock-, Endometrium- und Zervixkarzinom lag. Die Studie zeigte eine objektive Ansprechrate (ORR) von 27% und eine klinische Nutzenrate (CBR) von 33% mit einer medianen progressionsfreien Überlebenszeit (PFS) von 57 Wochen. Das Regime wurde gut vertragen, ohne schwerwiegende immunbedingte Nebenwirkungen. Die Studie, die sich in der Nähe der Vollendung befindet, wird drei weitere Patienten rekrutieren. Die Ergebnisse lassen darauf schließen, dass LYMPHIR die Wirksamkeit von Immun-Checkpoint-Inhibitoren wie Pembrolizumab erhöhen könnte. Die vielversprechenden Ergebnisse der Studie unterstützen die Ausweitung der Forschung in eine Phase-II-Studie zur Bewertung der Vorteile der Kombination in einem breiteren Bereich von soliden Tumoren.
- 27% Objective Response Rate (ORR) in the trial.
- 33% Clinical Benefit Rate (CBR) with a median PFS of 57 weeks.
- No significant immune-related adverse events documented.
- LYMPHIR may enhance the efficacy of pembrolizumab.
- One case of dose-limiting toxicity (capillary leak syndrome) at the highest dose level.
Insights
The preliminary Phase 1 trial results for LYMPHIR + pembrolizumab combination show significant promise. The 27% objective response rate and 33% clinical benefit rate in heavily pre-treated patients are particularly noteworthy. The median progression-free survival of 57 weeks is impressive for this patient population.
Two critical findings stand out: First, the combination demonstrated efficacy in patients who previously failed checkpoint inhibitor therapy, suggesting potential for treating resistant cases. Second, the favorable safety profile with no significant immune-related adverse events is remarkable for an immunotherapy combination.
The study's focus on gynecological cancers addresses substantial market opportunities - with over
The mechanism of action combining LYMPHIR's Treg depletion with pembrolizumab's PD-1 inhibition represents an innovative approach to immunotherapy. Most notably, achieving responses in checkpoint inhibitor-resistant patients suggests this combination could overcome a major limitation in current immunotherapy.
The safety profile is particularly encouraging - immunotherapy combinations often face challenges with overlapping toxicities, but this regimen shows minimal serious adverse events. The 57-week median PFS in responding patients indicates durable responses, which is important for clinical significance.
The dose-escalation design effectively established safety across multiple dose levels, though the single DLT at 12 mcg/kg warrants careful consideration for dose selection in Phase 2. The focus on gynecologic malignancies is well-justified given the significant unmet need in these indications.
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
Chemotherapy-free immunomodulatory regimen well-tolerated with no documented serious immune-related adverse events
The trial is being conducted by Haider Mahdi, M.D., Assistant Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, at the University of
"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
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 of33% (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) | |
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 theU.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
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 <3 g/dL. These symptoms were not required to occur simultaneously to be characterized as capillary leak syndrome.
As defined, CLS occurred in
Regularly assess patients for weight gain, new onset or worsening of edema, dyspnea, and hypotension (including orthostatic changes). Monitor serum albumin levels prior to the initiation of each cycle of therapy and more often as clinically indicated.
Withhold, reduce dose, or permanently discontinue based on severity. If LYMPHIR is withheld, resume LYMPHIR following resolution of CLS and when serum albumin is greater than or equal to 3 g/dL.
Visual Impairment
LYMPHIR can cause serious visual impairment, including changes in visual acuity and color vision. In the pooled population across 3 clinical trials, visual impairment occurred in
Perform baseline ophthalmic examination and monitor as clinically indicated. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, or blurred vision, refer for ophthalmologic evaluation.
Withhold LYMPHIR until visual impairment resolves or permanently discontinue based on severity.
Infusion-Related Reactions
LYMPHIR can cause serious infusion-related reactions. Infusion-related reactions were reported in
Premedicate patients for the first three cycles prior to starting a LYMPHIR infusion [see Dosage and Administration (2.3)]. Monitor patients frequently during infusion. For Grade 2 or higher infusion reactions, premedicate at least 30 minutes prior to each subsequent infusion with a systemic steroid for at least 3 cycles.
Interrupt or discontinue LYMPHIR based on severity [see Dosage and Administration (2.4)]. Institute appropriate medical management.
Hepatotoxicity
LYMPHIR can cause hepatotoxicity. In the pooled safety population, elevated ALT occurred in
Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold, reduce dose, or permanently discontinue LYMPHIR based on severity.
Embryo-Fetal Toxicity
Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to the initiation of LYMPHIR. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 days following the last dose of LYMPHIR.
ADVERSE REACTIONS
The most common adverse reactions (≥
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman. There are no available data on the use of LYMPHIR in pregnant women to evaluate for a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with denileukin diftitox.
Denileukin diftitox-cxdl causes depletion of regulatory T lymphocytes (Treg), immune activation, and capillary leak syndrome, compromising pregnancy maintenance. Advise pregnant women of the potential risk to a fetus.
In the
Lactation
Risk Summary
No data are available regarding the presence of denileukin diftitox-cxdl in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LYMPHIR and for 7 days after the last dose.
Females and Males of Reproductive Potential
Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman.
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating LYMPHIR.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with LYMPHIR and for 7 days after the last dose.
Infertility
Males
Based on findings in rats, male fertility may be compromised by treatment with. The reversibility of the effect on fertility is unknown.
Pediatric Use
Safety and effectiveness of LYMPHIR in pediatric patients have not been established.
Geriatric Use
Of the 69 patients with Stage I-III r/r CTCL who received LYMPHIR, 34 patients (
You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Citius Pharmaceuticals at 1-844-459-6744.
Please read Important Safety Information and full Prescribing Information, including Boxed WARNING, for LYMPHIR™.
Please see Prescribing Information for KEYTRUDA® (pembrolizumab) and Medication Guide for KEYTRUDA.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
About Citius Oncology, Inc.
Citius Oncology, Inc. (Nasdaq: CTOR) is a platform to develop and commercialize novel targeted oncology therapies. In August 2024, its primary asset, LYMPHIR, was approved by the FDA for the treatment of adults with relapsed or refractory CTCL who had had at least one prior systemic therapy. Management estimates the initial market for LYMPHIR currently exceeds
About Citius Pharmaceuticals, Inc.
Citius Pharmaceuticals, Inc. (Nasdaq: CTXR) is a biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products. In August 2024, the FDA approved LYMPHIR, a targeted immunotherapy for an initial indication in the treatment of cutaneous T-cell lymphoma. Citius Pharma's late-stage pipeline also includes Mino-Lok®, an antibiotic lock solution to salvage catheters in patients with catheter-related bloodstream infections, and CITI-002 (Halo-Lido), a topical formulation for the relief of hemorrhoids. A Pivotal Phase 3 Trial for Mino-Lok and a Phase 2b trial for Halo-Lido were completed in 2023. Mino-Lok met primary and secondary endpoints of its Phase 3 Trial. Citius is actively engaged with the FDA to outline next steps for both programs. Citius Pharmaceuticals owns
Forward-Looking Statements
This press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "plan," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated, and, unless noted otherwise, that apply to Citius Pharma and Citius Oncology, are: risks relating to the results of research and development activities, including those from our existing and any new pipeline assets; risks related to research using our assets but conducted by third parties; our need for substantial additional funds; Citius Pharma's ability to meet Nasdaq's continued listing standards; our ability to commercialize LYMPHIR and any of our other product candidates that may be approved by the FDA; the estimated markets for our product candidates and the acceptance thereof by any market; the ability of our product candidates to impact the quality of life of our target patient populations; our dependence on third-party suppliers; our ability to procure cGMP commercial-scale supply; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; uncertainties relating to preclinical and clinical testing; the early stage of products under development; market and other conditions; risks related to our growth strategy; patent and intellectual property matters; our ability to identify, acquire, close and integrate product candidates and companies successfully and on a timely basis; government regulation; competition; as well as other risks described in our SEC filings. These risks have been and may be further impacted by any future public health risks. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission ("SEC") filings which are available on the SEC's website at www.sec.gov, including in Citius Pharma's Annual Report on Form 10-K for the year ended September 30, 2023, filed with the SEC on December 29, 2023, Citius Oncology's Current Report on Form 8-K, filed with the Commission on August 16, 2024 (as amended by Amendment No. 1 to Form 8-K, filed on August 26, 2024), both as updated by our subsequent filings with the Securities and Exchange Commission. These forward-looking statements speak only as of the date hereof, and we expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.
Investor Relations for Citius Pharmaceuticals:
Investor Contact:
Ilanit Allen
ir@citiuspharma.com
908-967-6677 x113
Media Contact:
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