| 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 | 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
chemotherapy 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 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 ontreatment
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.
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 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 CLIAcertified
(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.
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.
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 | 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 8.
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 ,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).
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 (Groups C and E
only)
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.
Please refer to the protocol for more details | |
| 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 | No |
| 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 | No |
| 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 | 4 |
| 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 | 4 |
| 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 | | Belgium | | China | | France | | Georgia | | Germany | | Greece | | Italy | | United States | |
| 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. | |
| 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 | 1 |
| 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 |
