| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014733 |
| E.1.2 | Term | Endometrial cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014734 |
| E.1.2 | Term | Endometrial cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate antitumor activity of INCMGA00012 in Group A. |
|
| E.2.2 | Secondary objectives of the trial |
- To further evaluate clinical efficacy of INCMGA00012 monotherapy and evaluate clinical activity in the combinations.
- To evaluate the safety and tolerability of INCMGA00012 as monotherapy and in combination. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Ability to comprehend and willingness to sign a written ICF for the study.
2. Women 18 years of age or older (or as applicable per local country requirements).
3. 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 Nhemotherapy in an early disease stage is allowable. Prior hormonal therapy is allowable in any disease setting.
4. Groups A,B and E: Have not been previously treated with a PD-(L)1 inhibitor.
5. Group F: INCMGA00012 in combination with INCAGN02385 and INCAGN02390 in participants who have MSI-H advanced or metastatic endometrial cancer with evidence of disease progression on or following platinum-based chemotherapy and previous PD-(L)1 inhibitory therapy.
6. 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.
7. Group B only: Tumor tissue centrally tested as dMMR or locally tested as an ultra-mutated POLE tumor 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.
8. 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.
9. 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 enrollment. See Section 8.1.2.1 for assay details.
10. 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. See Section 8.1.2.1 for assay details.
11. 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.
12. Willing to provide tumor tissue sample (fresh or archived).
13. ECOG performance status 0 to 1.
14. 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 |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Groups A, B and E only: Histologically confirmed diagnosis of carcinosarcoma of the uterus.
2. Histologically confirmed diagnosis of sarcoma of the uterus.
3. Has disease eligible for potentially curative treatment with standard chemotherapy, surgical resection, or chemoradiotherapy.
4. Receipt of anticancer therapy within 28 days of the first administration of study treatment, with the exception of localized radiotherapy.
5. Toxicity of prior therapy that has not recovered to ≤ Grade 1 (with the exception of alopecia and anemia not requiring transfusional support), unless approved by the medical monitor.
6. 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).
7. Group F only: Previous treatment with LAG-3 or TIM-3 directed therapy or lenvatinib.
8. 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.
9. Participant with laboratory values at screening defined in Table 7.
10. 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.
11. Receiving chronic systemic corticosteroids(> 10 mg/day of prednisone or equivalent).
12. 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.
13. History of organ transplant, including allogeneic stem cell transplantation.
14. Receiving probiotics as of the first dose of study treatment.
15. Known active CNS metastases and/or carcinomatous meningitis.
16. 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.
17. Has known active hepatitis B or C (defined as follows) or HIV, HBV, HCV, or HDV coinfection.
18. Known hypersensitivity to any of the study drugs, excipients, or another monoclonal antibody that cannot be controlled with standard measures (eg, antihistamines and corticosteroids).
19. Participants with impaired cardiac function or clinically significant cardiac disease.
20. Women who are pregnant or breast-feeding.
21. If participant received major surgery, then they must have recovered adequately from toxicities and/or complications from the intervention before starting study treatment.
22. Has received a live vaccine within 28 days of the planned start of study treatment.
23. Evidence of interstitial lung disease or active, noninfectious pneumonitis.
24. Current use of prohibited medication as noted in Section 6.8.3.
25. 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.
26. Participants who are known to be HIV-positive.
27. For Group C, Group 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
28. History of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn's disease, ulcerative colitis) that may affect oral drug absorption.
29. Exclusion criteria specific to a group receiving combination therapy.
a. Participants enrolled in the epacadostat combination (Group C and E only): History of serotonin syndrome after receiving 1 or more serotonergic drugs.
b. Participants enrolled in the pemigatinib combination (Group D only)
30. 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Group A (INCMGA00012 monotherapy): ORR, defined as the proportion of participants having a CR or PR according to RECIST v1.1, will be determined by ICR. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Group A (INCMGA00012 monotherapy):
• DOR, defined as the time from the first documented objective response (CR or PR) according to RECIST v1.1 (as determined by ICR) until disease progression or death due to any cause.
• DCR, defined as the proportion of participants with CR, PR, or SD (as determined by ICR) as best response.
• PFS, defined as the time from the first dose of study treatment until disease progression (as determined by ICR) or death due to any cause.
• OS, defined as the time from the first dose of study treatment until death due to any cause.
All other groups:
• ORR, defined as the proportion of participants having a CR or PR according to RECIST v1.1 (as determined by the investigator).
Safety and tolerability will be assessed by monitoring the frequency and severity of AEs and SAEs as well as laboratory test results. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| China |
| United States |
| France |
| Germany |
| Greece |
| Italy |
| Belgium |
| Georgia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Treatment duration on study is up to 2 years in the absence of clinical progression or intolerable toxicity. The study will end once the last participant in each treatment group has been followed for approximately 6 months. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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