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TROPIC NEO

Targeting Response Of the hypoxia Pathway and Immune microenvironment in squamous Cancers of the head and neck in Neoadjuvant setting.

Acronym: TROPIC-Neo

Trial Design

A single arm, biomarker-defined phase 2 clinical trial for locally advanced head and neck squamous cell cancers treated with surgery with or without adjuvant therapy.

Inclusion criteria

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of locoregionally-advanced HNSCC will be enrolled in this study.
2. Patients must have an MDT recommendation for treatment with primary surgery.
3. Fulfils (TNM 8^th edition) criteria:

Oral or p16-negative oropharyngeal SCC:

• T3N0 – T4N0
• T1-T4, N1-N3

OR

p16 positive oropharyngeal SCC High risk:

• HPV positive smokers T1-T4 with one or more nodes >3cm or bilateral nodes, or a node >6cm
• Any p16 positive T4 or N3

4. The participant provides written informed consent for the trial.
5. Patient willing and able to comply with scheduled visits, treatment plan and other study procedures.
6. Recently (within 3 months) obtained biopsy [core, incisional or excisional] of a tumour lesion not previously irradiated is available for testing. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 28 days prior to the first dose of study intervention.
8. Have adequate organ function as defined in the following table. Samples must be collected within 10 days prior to the start of study intervention:

9. Female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
   • Is not a woman of child-bearing potential (WOCBP), OR
   • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in the Appendix during the intervention period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention.
   • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
   • If a urine test cannot be confirmed as negative (e.g., an ambiguous result), as serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy test is positive.
   • Additional requirements for pregnancy testing during and after study intervention are located in the Appendix.
   • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
   • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

10.Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have had no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

11. Male and female patients of childbearing potential willing to use highly effective contraception see section 7.7.

12. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of study intervention:

• • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent, OR
  • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [refer to Appendix]) as detailed below:
    1. Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
    2. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
    3. Male participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
  • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Exclusion criteria

1. T1-T2 N0 HPV positive or HPV negative HNSCC.
2. MDT recommendation for treatment by primary radiotherapy alone or chemoradiotherapy only.
3. Recurrent or metastatic HNSCC.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137).
5. Has received prior systemic anti-cancer therapy including investigational agents.
6. Has received any type of systemic anticancer antibody (including investigational antibody) ≤4 weeks trial entry.
7. Has received prior radiotherapy.
8. Has received prior treatment with Belzutifan or another HIF-2α inhibitor.
9. Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤2 weeks trial entry.
10. Has had major surgery ≤3 weeks prior to first dose of study intervention. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
11. Received colony-stimulating factors (e.g., G-CSF, GM-CSF or recombinant erythropoietin (EPO)) ≤28 days prior to the first dose of study intervention.
12. Has received an investigational agent within 4 weeks prior to study intervention administration.
13. Is currently participating in a study of an investigational agent. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
15. Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (Belzutifan) formulations.
16. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
17. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
18. Known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, e.g. breast carcinoma in situ, cervical cancer in situ - but excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.
19. Has known active CNS metastases and/or carcinomatous meningitis.
20. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction ≤6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted.
21. Has moderate to severe hepatic impairment (Child-Pugh B or C).
22. Has had an allogenic tissue/solid organ transplant.
23. Has any of the following:
    • A pulse oximeter reading <92% at rest, or
    • Requires intermittent supplemental oxygen, or
    • Requires chronic supplemental oxygen.
24. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid).
25. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
26. Has an active infection requiring systemic therapy.
27. History of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as detectable HCV RNA [qualitative]) infection. Note: Testing for Hepatitis B or C is not required unless mandated by local health authority.
28. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
29. Has a known history of HIV infection. Note: Testing for HIV at screening is only required if mandated by local health authority.
30. Has active TB.
31. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
32. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
33. Female patients who are breastfeeding.
34. Unfit for chemoradiotherapy regimens.
35. Administration of yellow fever vaccine within 30 days to surgery.
36. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
37. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. Note: A current list of strong/moderate inducers of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers

TROPIC-Neo Trial Office Contact Details

Cancer Research UK Clinical Trials Unit,

Institute for Cancer and Genomic Sciences,

University of Birmingham, Edgbaston,

Birmingham, B15 2TT

TROPIC-NEO@trials.bham.ac.uk