| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Male and female participants at least 18 years of age who have inoperable locally recurrent or metastatic Squamous Carcinoma of the Anal Canal (SCAC) not previously treated with systemic chemotherapy. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Squamous Carcinoma of the Anal Canal |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002127 |
| E.1.2 | Term | Anal canal cancer recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy (PFS) of carboplatin-paclitaxel with INCMGA00012 versus carboplatin-paclitaxel with placebo in participants with inoperable locally advanced or metastatic SCAC not previously treated with systemic chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the efficacy (OS) of carboplatin-paclitaxel with INCMGA00012 versus carboplatin-paclitaxel with placebo in participants with inoperable locally advanced or metastatic SCAC not previously treated with systemic chemotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to comprehend and willing to sign a written ICF for the study.
2. Are 18 years of age or older (or as applicable per local country requirements).
3. Histologically or cytologically verified, inoperable locally recurrent or metastatic SCAC.
4. No prior systemic therapy other than the following:
a. Chemotherapy administered concomitantly with radiotherapy as a radiosensitizing agent is permitted.
b. Prior neoadjuvant or adjuvant therapy if completed ≥ 6 months before study entry.
5. Has measurable disease per RECIST v1.1 as determined by local site investigator/radiology assessment. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.
6. Able and willing to provide adequate tissue sample and whole blood sample with central testing result prior to randomization. Biopsy for archival samples should have occurred within 6 months prior to randomization.
7. ECOG performance status 0 to 1.
8. If HIV-positive, then must be stable as defined by:
a. CD4+ count ≥ 300/μL,
b. Undetectable viral load per standard of care assay,
c. Receiving antiretroviral therapy (ART/HAART) for at least 4 weeks prior to study enrollment, and have not experienced any HIV-related opportunistic infection for at least 4 weeks prior to study enrollment.
9. Willingness to avoid pregnancy or fathering children based on the criteria below.
a. Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 120 days after the last dose of INCMGA00012 or placebo or through 180 days after the last dose of chemotherapeutic agents, whichever occurs later (or longer as appropriate based on country-specific requirements) and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
b. 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 120 days after the last dose of INCMGA00012 or placebo or through 180 days after the last dose of chemotherapeutic agents, whichever occurs later. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible. |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Has received prior PD-(L)1 directed therapy
2. Has received prior radiotherapy with or without radiosensitizing chemotherapy within 28 days of Cycle 1 Day 1 (note: all toxicities associated should have resolved to Grade ≤ 1).
3. Participants with laboratory values at screening defined in Table 8 of the protocol
4. Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 3 years of study entry with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, 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.
5. Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg of prednisone or equivalent).
6. Evidence of interstitial lung disease or active noninfectious pneumonitis.
7. History of organ transplant, including allogeneic stem cell transplantation.
8. Known active CNS metastases and/or carcinomatous meningitis, per Section 8.2.1.1.
9. Known active HAV, HBV, or HCV infection, as defined by elevated transaminases with the following serology: positivity for HAV IgM antibody, anti–HCV, anti–HBc IgG or IgM, or HBsAg (in the absence of prior immunization).
10. Active infections requiring systemic therapy, or systemic antibiotic use up to 28 days before Cycle 1 Day 1.
11. Known hypersensitivity to platinum, paclitaxel, another monoclonal antibody, or any of the excipients that cannot be controlled with standard measures (eg, antihistamines, corticosteroids).
12. Participants with impaired cardiac function or clinically significant cardiac disease:
a. New York Heart Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, or cardiomyopathy.
b. Unstable angina pectoris.
c. Acute myocardial infarction ≤ 6 months before study participation.
d. Other clinically significant heart disease (ie, ≥ uncontrolled Grade 3 hypertension or high-grade conduction disturbance.)
13. Participant is pregnant or breastfeeding.
14. Has received a live vaccine within 28 days of Cycle 1 Day 1.
Note: Examples of live vaccines include but are not limited to measles, mumps, rubella, chicken pox/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live-attenuated vaccines and are not allowed.
15. Current use of prohibited medication as specified in Section 6.6.2.
16. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v5.
17. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from the date of randomization until disease progression according to RECIST v1.1 by BICR or death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Imaging and response assessment should be performed every 8 weeks (56 days ± 7 days) until the Week 56 assessment and then every 12 weeks (84 days ± 7 days) during the Crossover Period or Disease Follow-Up Period as appropriate until second disease progression, withdrawal of consent, death, or notification to site by the sponsor, whichever occurs first.
|
|
| E.5.2 | Secondary end point(s) |
OS, defined as the time from the date of randomization until death due to any cause.
ORR, defined as the percentage of participants having a CR or PR, according to RECIST v1.1 as determined by BICR.
DOR, defined as the time from the first documented response (CR or PR) according to RECIST v1.1 until disease progression as determined by BICR or death due to any cause.
DCR, defined as the number of participants maintaining either an ORR or stable disease.
Number of participants experiencing AEs and number of participants discontinuing study drug due to AEs. |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Australia |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Norway |
| Spain |
| United Kingdom |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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