INCMGA 0012-204: An Umbrella Study of INCMGA00012 Alone and in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-Based Chemotherapy (POD1UM-204)
- Trial ID
- 2022-502600-79-00
- Protocol
- INCMGA0012-204
- Sponsor
- Incyte Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **antitumor activity** of INCMGA00012 in Group A. This is clinically relevant as it aims to determine the efficacy of INCMGA00012 in treating advanced or metastatic **endometrial cancer**, particularly in patients who have progressed following platinum-based chemotherapy. Understanding the antitumor activity is crucial for assessing the potential of INCMGA00012 as a therapeutic option for this patient population.
Secondary objectives include:
- To further evaluate the clinical efficacy of INCMGA00012 monotherapy and assess its clinical activity when used in combination with other therapies. This is important for understanding the broader therapeutic potential and optimizing treatment regimens.
- To evaluate the safety and tolerability of INCMGA00012 both as a monotherapy and in combination. This is essential for ensuring patient safety and determining the risk-benefit profile of the treatment.
Participants
The clinical trial involves a total of **69 participants** diagnosed with **endometrial cancer**. The study population is exclusively female, with an age range that includes adults and older adults. Participants were selected based on specific inclusion criteria, including a histologically confirmed diagnosis of advanced or metastatic endometrial cancer with disease progression following at least one platinum-containing regimen. The trial does not include male subjects, and it involves a vulnerable population. Participants are required to have an **ECOG performance status** of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified in the available data. The selection process ensures that participants have measurable tumor lesions and are willing to provide tumor tissue samples. The trial focuses on evaluating the antitumor activity of INCMGA00012 in a specific group, with participants having not been previously treated with a PD-(L)1 inhibitor, except for those in Group F who must have shown disease progression on or after prior PD-(L)1 therapy.
Plans and Procedures
The clinical trial is designed to evaluate the **antitumor activity** of **Retifanlimab** (INCMGA00012) in participants with advanced or metastatic **endometrial cancer** who have progressed on or after platinum-based chemotherapy. This is a Phase 2, randomized, double-blind, controlled trial with an estimated duration extending until May 31, 2026. The trial involves multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as histologically confirmed diagnosis and measurable tumor lesions per RECIST v1.1. Participants will be required to provide a tumor tissue sample and demonstrate an **ECOG performance status** of 0 to 1.
Following the screening, participants will be randomized into different groups to receive either **Retifanlimab** monotherapy or in combination with other therapies. The trial includes regular follow-up visits to monitor the **objective response rate (ORR)**, **duration of response (DOR)**, **disease control rate (DCR)**, **progression-free survival (PFS)**, and **overall survival (OS)**. Safety and tolerability will be assessed by monitoring adverse events and laboratory test results. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the primary and secondary endpoints.
Participant involvement is expected to last up to 104 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial is not categorized as low intervention and is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants. The trial's design and methodology are structured to provide robust data on the efficacy and safety of the investigational product in the specified patient population.
Treatment
The clinical trial involves the administration of **Retifanlimab** (INCMGA00012), a **solution for infusion**. This experimental medication is administered **intravenously**. The maximum daily dose is 500 mg, with a total maximum dose of 13,000 mg over a treatment period of up to 104 weeks. Retifanlimab is a protein-based therapeutic agent developed by Incyte Corporation, specifically designed for participants with advanced or metastatic endometrial cancer who have progressed on or after platinum-based chemotherapy.
**Pemazyre** 4.5 mg tablets, containing the active substance **Pemigatinib**, are also utilized in this study. Pemigatinib is a chemical compound administered **orally**. The maximum daily dose is 13.5 mg, with a total maximum dose of 9,828 mg over the same treatment period of 104 weeks. This medication is provided by Incyte Biosciences Distribution B.V. and serves as a comparator treatment in the trial.
Another investigational product, **INCAGN02390**, is a **solution for infusion** containing a **human IgG1k monoclonal antibody against TIM-3**. This biological agent is administered **intravenously**. The maximum daily dose is 400 mg, with a total maximum dose of 20,800 mg over 104 weeks. Developed by Incyte Corporation, this treatment is part of the combination therapy being evaluated in the study.
Lastly, the trial includes **INCAGN02385**, a **solution for infusion** containing the protein-based substance **Tuparstobart**. This investigational drug is administered **intravenously**. The maximum daily dose is 350 mg, with a total maximum dose of 18,200 mg over the 104-week treatment period. Incyte Biosciences International Sàrl is responsible for the development of this biological agent, which is also part of the combination therapy under investigation.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint for Group A, which involves **INCMGA00012** monotherapy, is the Objective Response Rate (ORR). This is defined as the proportion of participants achieving a Complete Response (CR) or Partial Response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as determined by Independent Central Review (ICR).
Secondary endpoints for Groups A and B include Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS). DOR is defined as the time from the first documented objective response (CR or PR) until disease progression or death from any cause. DCR is the proportion of participants with CR, PR, or Stable Disease (SD) as the best response. PFS is the time from the first dose of study treatment until disease progression or death from any cause. OS is the time from the first dose of study treatment until death from any cause.
For all other groups, ORR will be assessed as the proportion of participants achieving CR or PR according to RECIST v1.1, as determined by the investigator. Safety and tolerability will also be evaluated by monitoring the frequency and severity of adverse events (AEs) and serious adverse events (SAEs), along with laboratory test results.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Ability to comprehend and willingness to sign a written ICF for the study
- Group F only: Tumor tissue tested as MSI-H centrally or locally using PCR assay. MSI H results obtained locally would need to be subsequently confirmed centrally after participant's enrollment.
- Must have at least 1 measurable tumor lesion per RECIST v1.1. Note: Lesions to be used as measurable disease for the purpose of response assessment must either a) not reside in a field that has been subjected to prior radiotherapy, or b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study enrollment.
- Women 18 years of age or older (or as applicable per local country requirements).
- Histologically confirmed diagnosis of advanced or metastatic endometrial cancer with disease progression on or after treatment with at least 1 platinum-containing regimen for advanced or metastatic disease. Note: for Group E only: No more than 1 systemic regimen for advanced or metastatic disease is allowed. For all groups neoadjuvant chemotherapy in an early disease stage is allowable. Prior hormonal therapy is allowable in any disease setting.
- Groups A, B and E: Have not been previously treated with a PD-(L)1 inhibitor.
- Group F only: Radiological evidence of disease progression on or after prior PD (L)1 therapy. Participant must have received at least 2 doses of prior PD-(L)1 therapy. Participant may have received PD-(L)1 therapy either alone or in combination. Disease progression must have occurred on or after the first on treatment scan and must have been confirmed subsequently by imaging ≥ 4 weeks after evidence of initial disease progression. Note: baseline scan within the study may serve as a confirmatory scan for progressive disease. Participant may have achieved objective response (CR or PR) to prior PD-(L)1 therapy followed by disease recurrence.
- Group A only: Tumor tissue centrally tested as MSI-H using Promega OncoMate™ MSI Dx assay. See Section 8.1.2.1 for assay details.
- Group B only: Tumor tissue centrally tested as dMMR using MMR IHC assay or known to have ultra-mutated POLE tumor per locally available result. See Section 8.1.2.1 for assay details. Note: POLE ultra-mutated participants need to have documented POLE exonuclease domain mutation (residues 268-471) known to have damaging effect on exonuclease domain function. Test type (eg, PCR or NGS) should be documented in the EDC.
- Group D only: Tumor tissue tested locally or centrally, based on CLIA certified (or similar certification) laboratory assays, as having FGFR1-3 fusions or rearrangements characterized as follows: a. FGFR1-3 in-frame fusions, b. any FGFR2 rearrangement, or c. FGFR1-3 rearrangement with known partner. Note: See Appendix C for most detailed information on FGFR fusions and/or rearrangements allowed.
- Group E only:Tumor tissue centrally tested as PD-L1–positive using Ventana SP263 assay (determined based on PD-L1 staining of TCs, ICs, and ICPs and tested as MSS locally or centrally using PCR assay. Microsatellite stability results obtained locally would need to be subsequently confirmed centrally after participant's enrolment.
- Willing to provide tumor tissue sample (fresh or archived).
- ECOG performance status 0 to 1.
- Willingness to avoid pregnancy based on the criteria below. a. Women of childbearing potential must have a negative serum pregnancy test at screening and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through 6 months after the last dose of study treatment and must refrain from donating oocytes during this period. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed (See Appendix A). b. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy
Exclusion Criteria
- Groups A,B and E only: Histologically confirmed diagnosis of carcinosarcoma of the uterus.
- Histologically confirmed diagnosis of sarcoma of the uterus.
- Has disease eligible for potentially curative treatment with standard chemotherapy, surgical resection, or chemoradiotherapy.
- Receipt of anticancer therapy within 28 days of the first administration of study treatment, with the exception of localized radiotherapy.
- Toxicity of prior therapy that has not recovered to ≤ Grade 1 (withthe exception of alopecia and anemia not requiring transfusional support), unless approved by the medical monitor.
- Groups C ,D and F (combinations): Immune-related toxicity during prior checkpoint inhibitor therapy for which permanent discontinuation of therapy is recommended (per product label or consensus guidelines), OR severe immune-related toxicity requiring intensive (eg, use of infliximab) or prolonged immunosuppression (eg, > 6 weeks) to manage (with the exception of endocrinopathy that is well-controlled on replacement hormones).
- Group F only: Previous treatment with LAG-3 or TIM-3 directed therapy or lenvatinib.
- Group F only: Participants with multiple metastases that achieved mixed tumor response to prior anti–PD-(L)1 therapy (such as isolated progressive lesion in a context of PR/CR or SD for other lesions) or achieved overall disease progression based only on a single new lesion.
- Participant with laboratory values at screening defined in Table 8
- Has an active autoimmune disease requiring systemic immunosuppression with corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs within 14 days before the first dose of study treatment.
- Receiving chronic systemic corticosteroids(> 10 mg/day of prednisone or equivalent).
- Active infections requiring systemic antibiotics or antifungal or antiviral treatment (except where warranted as per Exclusion Criteria 17 and 26) within 7 days before first dose of study treatment.
- History of organ transplant, including allogeneic stem cell transplantation.
- Receiving probiotics as of the first dose of study treatment.
- Known active CNS metastases and/or carcinomatous meningitis.
- Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, or cancers from which the participant has been disease-free for > 1 year, after treatment with curative intent.
- Has known active hepatitis B or C (defined as follows) or HIV, HBV, HCV, or HDV coinfection.
- Known hypersensitivity to any of the study drugs, excipients, or another monoclonal antibody that cannot be controlled with standard measures (eg, antihistamines and corticosteroids).
- Participants with impaired cardiac function or clinically significant cardiac disease.
- Women who are pregnant or breast-feeding.
- If participant received major surgery, then they must have recovered adequately from toxicities and/or complications from the intervention before starting study treatment.
- Has received a live vaccine within 28 days of the planned start of study treatment.
- Evidence of interstitial lung disease or active, noninfectious pneumonitis.
- Current use of prohibited medication as noted in Section 6.8.3.
- Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
- Participants who are known to be HIV-positive.
- For Group C ,D and E : History or presence of an abnormal ECG that in the investigator's opinion, is clinically meaningful. Average QTc interval > 480 milliseconds is excluded (corrected by Fridericia or Bazett formula).
- History of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn's disease, ulcerative colitis) that may affect oral drug absorption.
- Exclusion criteria specific to a group receiving combination therapy. a. Participants enrolled in the epacadostat combination (Groups C and E only) b. Participants enrolled in the pemigatinib combination (Group D only)
- The following participants are excluded in France: vulnerable populations according to article L.1121-6 of the French Public Health Code and adults under legal protection, or who are unable to express their consent per article L.1121-8 of the French Public Health Code, not affiliated to a social security per article L.1121-8-1 of the French Public Health Code.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 09 Apr 2021 | 13 |
 France | Not Recruiting | 09 Apr 2021 | 37 |
 Greece | Not Recruiting | 09 Apr 2021 | 12 |
 Italy | Not Recruiting | 09 Apr 2021 | 26 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
INCAGN02390 | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 400 | 104 | PRD10013206 |
Pemazyre 4.5 mg tablets | Test | TABLETS | ORAL USE | 13.5 | 104 | PRD8840284 |
RetifanlimabINCMGA00012 | Test | SOLUTION FOR INFUSION | INTRAVENOUS | 500 | 104 | PRD6569529 |
INCAGN02385 | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 350 | 104 | PRD6569350 |