Oral AHR Antagonist in Combination With Nivolumab in Patients With PD-1 Resistant Metastatic or Recurrent Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
This is a phase 1b study in adult patients diagnosed with resistant or recurrent head and neck squamous cell carcinoma (HNSCC) designed to assess the safety and tolerability of IK-175 in combination with nivolumab. Disease response, pharmacokinetics (PK), pharmacodynamics, and response biomarkers will also be assessed.

Detailed Description
-----------------
This is an open-label, multicenter, phase 1b dose-expansion study to evaluate the safety, tolerability, preliminary antitumor activity, PK, and pharmacodynamics of 2 dose levels of IK-175, administered PO in combination with nivolumab, in patients with primary PD-1-resistant metastatic or locally incurable, recurrent HNSCC for which standard therapy is no longer effective or is intolerable.

Official Title
-----------------
A Phase 1b, Open-Label, Single-Arm Dose-Expansion Study of IK-175, an Oral Aryl Hydrocarbon Receptor Inhibitor, in Combination With Nivolumab in Patients With Primary PD-1 Inhibitor Resistant Metastatic or Locally Incurable, Recurrent HNSCC

Conditions
-----------------
Head Cancer, Neck Cancer, Head and Neck Squamous Cell Carcinoma, Head and Neck Cancer, Head Cancer Neck, Neck Carcinoma

Intervention / Treatment
-----------------
* Drug: IK-175 + nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Subject has a histologically confirmed metastatic or locally incurable, recurrent HNSCC that has progressed within 12 weeks of initiation of PD-1 inhibitor agent, whether it was administered alone or in combination with chemotherapy. Tumors must express PD-L1 with a minimum CPS ≥ 1. Subjects can be enrolled regardless of their tumor's expression of human papillomavirus (HPV). Subjects are required to have received prior treatment with a platinum-based chemotherapy in the recurrent or metastatic disease setting, unless medically contraindicated. Subject has at least 1 measurable lesion per RECIST v1.1. Key Exclusion Criteria: Subject has untreated or symptomatic central nervous system (CNS) tumors or brain metastases. Subject must have recovered to ≤ Grade 1 from clinically significant AEs related to prior therapy (eg, myelosuppression or renal or hepatic dysfunction.) Subject has received prior treatment with an AHR inhibitor. Subject has a medical condition that limits oral administration or impairment of gastrointestinal function that is expected to significantly reduce the absorption of IK-175. Uncontrolled or life-threatening symptomatic concomitant disease. Clinically significant cardiovascular disease as defined in the protocol. Subject is on a medication that is a sensitive substrate of CYP2C8, 2C9, 2C19, or 3A4 that cannot be substituted. Females who are pregnant or breastfeeding. Other inclusion/exclusion criteria are listed in the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized 1:1 to Cohort 1 or Cohort 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>600 mg qd PO IK-175 + nivolumab | Drug: IK-175 + nivolumab<br>* IK-175 + nivolumab<br>|
| Experimental: Cohort 2<br>450 mg q12h PO IK-175 + nivolumab | Drug: IK-175 + nivolumab<br>* IK-175 + nivolumab<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of treatment emergent adverse events (TEAEs) in subjects receiving IK-175 in combination with nivolumab [Safety and Tolerability] | Number and severity of TEAEs as assessed by CTCAE 5.0 | Treatment Period (Approximately 18 months) | 
| Frequency and severity of treatment related adverse events (TRAEs) in subjects receiving IK-175 in combination with nivolumab [Safety and Tolerability] | Number and severity of TRAEs as assessed by CTCAE 5.0 | Treatment Period (Approximately 18 months) | 
| Frequency and severity of serious adverse events (SAEs) in subjects receiving IK-175 in combination with nivolumab [Safety and Tolerability] | Number and severity of SAEs as assessed by CTCAE 5.0 | Treatment Period (Approximately 18 months) | 
| Frequency and severity of adverse events leading to dose modifications and/or treatment discontinuation in subjects receiving IK-175 in combination with nivolumab [Safety and Tolerability] | Number and severity of adverse events leading to dose modifications and/or treatment discontinuation as assessed by CTCAE 5.0 | Study Treatment Period (Approximately 18 months) | 
| Preliminary antitumor activity of IK-175 treatment in combination with nivolumab: Objective response rate (ORR) | ORR is defined as the percentage of participants with confirmed complete response (cCR) or confirmed partial response (cPR) per RECIST 1.1 | Through study completion including the Treatment Period (approximately 18 months) and the Follow-Up Period (Up to 6 months) | 
| Preliminary antitumor activity of IK-175 treatment in combination with nivolumab: Disease control rate (DCR) | DCR is defined as the percentage of participants with no occurrence of progressive disease with either cCR, cPR, or stable disease [SD] ≥ 16 weeks per RECIST 1.1 from the beginning of study therapy | Through study completion including the Treatment Period (approximately 18 months) and the Follow-Up Period (Up to 6 months) | 
| Preliminary antitumor activity of IK-175 treatment in combination with nivolumab: Duration of response (DOR) | DOR is defined as the time from the first documented CR or PR per RECIST 1.1 until disease progression or death from any cause | Through study completion including the Treatment Period (approximately 18 months) and the Follow-Up Period (Up to 6 months)) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of IK-175 when administered in combination with nivolumab: half-life (t1/2) | Determine IK-175 half-life (t1/2) | Time Frame: Day 1, 2, 15 of Cycle 1, Day 1 of Cycles 2-3 (every 28 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 56 days) through end of treatment (approximately 18 months) | 
| PK of IK-175 when administered in combination with nivolumab: area under the plasma concentration-time curve (AUC) | Determine IK-175 AUC | Time Frame: Day 1, 2, 15 of Cycle 1, Day 1 of Cycles 2-3 (every 28 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 56 days) through end of treatment (approximately 18 months) | 
| PK of IK-175 when administered in combination with nivolumab: maximum serum concentration (Cmax) | Determine IK-175 Cmax | Time Frame: Day 1, 2, 15 of Cycle 1, Day 1 of Cycles 2-3 (every 28 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 56 days) through end of treatment (approximately 18 months) | 
| PK of IK-175 when administered in combination with nivolumab: minimum serum concentration (Cmin) | Determine IK-175 Cmin | Time Frame: Day 1, 2, 15 of Cycle 1, Day 1 of Cycles 2-3 (every 28 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 56 days) through end of treatment (approximately 18 months) | 
| Preliminary antitumor activity of IK-175 in combination with nivolumab: Progression-free survival (PFS) median and at 6 months | PFS is defined as the length of time from the beginning of study treatment to the first observed disease progression or death due to any cause | Through study completion including the Treatment Period (approximately 18 months) and the Follow-Up Period (Up to 6 months) | 
| Preliminary antitumor activity of IK-175 in combination with nivolumab: Overall survival (OS), median and at 6 months | OS is defined as the length of time from the beginning of study treatment to the date of death due to any cause | Through study completion including the Treatment Period (approximately 18 months) and the Follow-Up Period (Up to 12 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Antagonist, aPD1, IK-175, AHR antagonist, AHR inhibitor, Aryl Hydrocarbon Receptor Antagonist, Immunooncology, AHRi, Aryl Hydrocarbon Receptor Inhibitor, Inhibitor, anti-PD1, nivolumab, checkpoint inhibitor, CPI, combination therapy