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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head Cancer; Neck Cancer; Head Cancer Neck; Neck Carcinoma
• Intervention / Treatment: Drug: IK-175 + nivolumab

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.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 600 mg qd PO IK-175 + nivolumab	Drug: IK-175 + nivolumab; IK-175 + nivolumab
Experimental: Cohort 2; 450 mg q12h PO IK-175 + nivolumab	Drug: IK-175 + nivolumab; IK-175 + nivolumab

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)

Collaborators and Investigators

• Sponsor: Ikena Oncology
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: Katherine Kim, MD, Ikena Oncology; Study Chair: Karim Malek, MD, Ikena Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2023
• Primary Completion (Estimated): April 1, 2023
• Study Completion (Estimated): April 1, 2023

Study Registration Dates

• First Submitted: July 20, 2022
• First Submitted That Met QC Criteria: July 22, 2022
• First Posted (Actual): July 25, 2022

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: combination therapy; nivolumab; checkpoint inhibitor; Inhibitor; IK-175; AHR antagonist; AHR inhibitor; Aryl Hydrocarbon Receptor Antagonist; Immunooncology; AHRi; Aryl Hydrocarbon Receptor Inhibitor; Antagonist; anti-PD1; aPD1; CPI
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Carcinoma; Squamous Cell Carcinoma of Head and Neck; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: IK175-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No