InterAACT 2

1. Able to comprehend and willing to sign a written Informed Consent 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 squamous cell carcinoma of the anal canal (SCAC).

4. No prior systemic therapy other than the following:

a. Chemotherapy administered concomitantly with radiotherapy as a radio-sensitising 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. Tumour 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 randomisation. Biopsy for archival samples should have occurred within 6 months prior to randomisation.

7. Eastern Cooperative Oncology Group (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 of the protocol) 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 of the protocol) 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 amenorrhoea and at least 50 years of age) are eligible. 

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 radio-sensitising 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 central nervous system (CNS) metastases and/or carcinomatous meningitis, per Section 8.2.1.1 of the protocol.

9. Known active hepatitis A virus (HAV), hepatitis B virus (HBV), or hepatitis C virus (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 immunisation).

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 pre-existing 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, Bacillus Calmette–Guérin (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 of the protocol.

16. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (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. 

Research Nurse: Haiyan Huang (Nolly) (x3766) Haiyan.Huang@lthtr.nhs.uk

Administrator: Rob Speirs (x8475)