Phase 2/3 Randomized Study of INBRX-106 Add-on to Pembrolizumab in First-Line PD-L1 CPS ≥20 R/M HNSCC (HexAgon-HN)

Prior treatment

• Receiving systemic steroids (>10 mg oral prednisone per day or equivalent) or other immunosuppressive agents within 7 days prior to randomization or has a diagnosis of immunodeficiency.
• History of toxicity ≥Grade 3 related to prior immunotherapy leading to treatment discontinuation, or toxicity related to any prior treatment that has not resolved to ≤Grade 1 (except alopecia, hearing loss, endocrinopathy managed with replacement therapy, and Grade ≤2 peripheral neuropathy or other toxicities not considered a safety risk per Investigator’s judgment).
• Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection within 14 days prior to randomization. • Patients who fully recovered from serious or clinically significant infections at least 14 days prior to randomization are eligible.
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease. • Patients with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Prior systemic therapy (eg, prior chemo-, immune-, or biologic therapy) for recurrent or metastatic HNSCC. • Prior systemic therapy completed >6 months prior to signing informed consent is allowed if given as part of multimodal treatment for locoregionally advanced disease with curative intent, and no PD/recurrence occurred within 6 months of its completion. Prior systemic immunotherapy for locoregionally advanced disease with curative intent, including but not limited to anti-PD-(L)1 agents, is allowed if PD/recurrence occurred ≥12 months after its completion.
• Treatment with any investigational systemic therapy within 28 days prior to randomization, or within 5 half-lives of the investigational drug(s), whichever is longer.
• Radiotherapy or any locoregional anticancer therapy within 14 days prior to randomization.
• Major surgical procedure or significant traumatic injury within 28 days prior to randomization. Patients must have also fully recovered from any surgery (major or minor) and/or its complications before randomization.
• Live vaccine administered within 30 days prior to randomization.

Other illness

• Disease amenable for local therapy administered with curative intent.
• Active tumor bleeding.
• Rapidly progressing disease or with features that may confer a high risk of tumor associated hemorrhage (including, but not limited to, tumors encasing or infiltrating a major vessel such as carotid, jugular, and bronchial artery, and/or other high-risk features such as an arteriovenous fistula), or uncontrolled tumor pain. The Sponsor’s Medical Monitor is available for consultation.
• Known allergy or hypersensitivity to INBRX-106, pembrolizumab, or any component of their respective formulations. History of severe hypersensitivity to protein-based therapies, in particular CHO-cell derived antibodies or other mAbs.
• Current or history of immune-related disease (refer to Appendix B) that required systemic treatment in past 2 years, except for replacement therapy (eg, physiological doses of corticosteroids for treatment of endocrinopathies).
• History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
• History of organ allograft transplantations or allogeneic peripheral blood stem cell transplantation/bone marrow transplantations.
• History of other invasive malignancy within 5 years prior to screening, except for cancers with very low risk of recurrence including, but not limited to, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, papillary thyroid cancer treated with surgery, or Stage I endometrial cancer. The Sponsor’s Medical Monitor is available for consultation.
• Known HIV infection, or positive test for active infection with HBV (eg, hepatitis B surface antigen [HBsAg] and/or total hepatitis B core antibody [HBcAb]) or HCV (eg, RNA). • Patients cured of HCV infection (undetectable viral load, sustained virologic response for 3 months after completing treatment), or positive for HCV antibody and negative for HCV RNA are eligible. Patients who are HCV carriers and test positive for HCV RNA are not eligible. • For patients who have been successfully treated for viral hepatitis, the possibility of re-activation of the virus or reinfection with viral hepatitis should be considered by the Investigator and the overall potential benefits associated with study treatment for the patient should be deemed to exceed the overall risks.
• Progressive disease within 6 months of completion of curatively intended treatment for locoregionally advanced HNSCC.

Lab values

• History or current evidence of any condition, therapy, or laboratory abnormality that in the Investigator’s opinion precludes the individual’s safe participation in and completion of the study.

Other

• Life expectancy <3 months.
• Primary tumor site (any histology) of nasopharynx or salivary glands or occult primary site.
• Personal or financial relationship with the Sponsor, a contractual relationship with the Investigator or the study site, or in custody or sanctioned by an official or court order.

• Able to understand and provide written informed consent.
• Life expectancy of >3 months.
• Adequate organ function, based on screening laboratory tests performed within 3 days of randomization, as defined by the following criteria: a. Hematological (without transfusion or growth factor support)  Absolute neutrophil count (ANC) ≥1.5x 109/L (1500/µL).  Platelet count ≥100x109/L (100,000/µL).  Hemoglobin ≥90 g/L (9 g/dL) or ≥5.6 mmol/L. b. Renal  Creatinine (Cr) ≤1.5 x upper limit of normal (ULN) OR  Creatinine clearance (CrCl) ≥30 mL/min estimated per institutional standard for patients with creatinine levels >1.5 x ULN (estimated glomerular filtration rate may be used instead of Cr or CrCl). c. Hepatic  Albumin ≥2.5 g/dL.  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN; for patients with liver metastases, ≤5 x ULN.  Serum bilirubin ≤1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). d. Coagulation  International normalized ratio (INR) (or prothrombin time [PT]) <1.5 x ULN, unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.  PTT (or activated PTT [aPTT]) <1.5 x ULN, except for patients receiving anticoagulants.
• Female patients of childbearing potential must have a negative highly sensitive pregnancy test within 72 hours prior to randomization and must not be breastfeeding.
• Fertile male patients and female patients of childbearing potential must be willing to completely abstain from heterosexual sex or agree to use acceptable contraception methods from the time of signing informed consent and for the duration of study treatment through 120 days following the last dose. See Appendix C of full protocol for detailed information on fertility, childbearing potential, and acceptable contraception.
• Ability, in the Investigator’s judgment, and willingness to adhere to the study visit schedule and comply with all study specific procedures.
• Age ≥18 years at the time of signing informed consent (minimum age requirement per local regulatory requirements).
• Histological or cytological documentation of HNSCC diagnosed as R/M and considered incurable by local therapies.
• Primary tumor location of the oral cavity, oropharynx, hypopharynx, or larynx.
• Consent to provide the most recently collected and representative tumor tissue specimen suitable for biomarker testing.
• Confirmed PD-L1 CPS ≥20, as assessed centrally using the PD-L1 IHC 22C3 pharmDx assay on the most recent tumor tissue specimen.
• Confirmed HPV tumor status for oropharyngeal cancer, as assessed centrally by p16 IHC testing on the most recent tumor tissue specimen. • Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing.
• Measurable disease per RECIST v1.1 guidelines. • Tumor lesion(s) previously irradiated or subjected to other locoregional therapy will be considered measurable only if PD is clearly documented at the lesion(s) after completion of therapy.
• ECOG PS score of 0-1.