Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)

Official title

An Open-Label, Multicenter, First-in-Human, Dose-Escalation, Multicohort, Phase 1/2 Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab in Subjects With Locally Advanced or Metastatic Solid Tumors

Overview

This is a Phase 1/2, open-label, non-randomized, 4-part trial to determine the safety profile and identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of INBRX 106 administered as a single agent or in combination with the anti-PD-1 checkpoint inhibitor (CPI) pembrolizumab (Keytruda®). KEYTRUDA is a registered trademark of Merck Sharp \& Dohme LLC, a subsidiary of Merck \& Co., Inc., Rahway, NJ, USA.

Interventions

• Drug INBRX-106 - Hexavalent OX40 agonist antibody
  The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).
• Drug pembrolizumab 200 mg
  pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.
• Drug pembrolizumab 400 mg
  pembrolizumab 400 mg by IV infusion given on Day 1 of alternating 21-day cycles (every 6 weeks)
• Drug Carboplatin AUC-5
  carboplatin AUC-5 by intravenous (IV) infusion, given on Day 1 of each 21-day cycle of cycles 1-4. Cohort F8, carboplatin AUC-5 by intravenous (IV) infusion, given on Day 1 of each 21-day cycle of cycle 2-4.
• Drug Carboplatin AUC-6
  carboplatin AUC-6 by intravenous (IV) infusion, given on Day 1 of each 21-day cycle of cycles 1-4
• Drug Pemetrexed 500 mg/m2
  pemetrexed 500 mg/m2 by IV infusion given on Day 1 of each 21-Day cycle for up to 35 cycles. In Cohort F8, pemetrexed 500 mg/m2 by IV infusion given on Day 1 of each 21-Day cycle of cycles 1-4.
• Drug Cisplatin 75mg/m2
  cisplatin 75mg/m2 by intravenous (IV) infusion, given on Day 1 of each 21-day cycle of cycles 1-4
• Drug Paclitaxel 200mg/m2
  paclitaxel 200mg/m2 by intravenous (IV) infusion, given on Day 1 of each 21-day cycle of cycles 1-4
• Drug Nab paclitaxel 100mg/m2
  Nab paclitaxel 100mg/m2 by intravenous (IV) infusion, given on Days 1, 8 and 15 of each 21-day cycle of cycles 1-4
• Drug Gemcitabine (1000 mg/m2)
  Gemcitabine 1000 mg/m2 given by intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle of cycles 1-4

Primary outcome measures

• Frequency of adverse events of INBRX-106 as single agent and in combination with pembrolizumab [Time frame: ~2 years]
• Severity of adverse events of INBRX-106 as single agent and in combination with pembrolizumab [Time frame: ~2 years]
• MTD and/or RP2D of INBRX-106 as single agent and in combination with pembrolizumab [Time frame: ~2 years]
• Antitumor activity of INBRX-106 in combination with pembrolizumab in expansion cohorts [Time frame: ~2 years]
• Frequency and severity of adverse events of INBRX-106 in combination with pembrolizumab and chemotherapy in adults with locally advanced or metastatic NSCLC or resectable Stage II, IIIA or IIIB (T3-4N2) NSCLC [Time frame: ~2 years]
• To assess the antitumor activity of INBRX-106 in combination with pembrolizumab and platinum doublet chemotherapy as neoadjuvant/adjuvant therapy in adult subjects with NSCLC. (Cohort F8) [Time frame: ~2 years]

Secondary outcome measures (5)

• Area under the serum concentration time curve (AUC) of INBRX-106 [Time frame: ~2 years]
• Maximum observed serum concentration (Cmax) of INBRX-106 [Time frame: ~2 years]
• Trough observed serum concentration (Ctrough) of INBRX-106 [Time frame: ~2 years]
• Time to Cmax (Tmax) of INBRX-106 [Time frame: ~2 years]
• Immunogenicity of INBRX-106 [Time frame: ~2 years]

Eligibility criteria

Select Inclusion Criteria:

• Males or females aged ≥18 years.
• Parts 1 and 3 (escalation cohorts): Subjects with locally advanced or metastatic non resectable solid tumors, whose disease has progressed despite all standard therapies or for whom no further standard or clinically acceptable therapy exists.
• Part 2 (single-agent expansion cohort): Subjects with NSCLC, melanoma, HNSCC, G/GEA, RCC, or TCC, with histologically confirmed, locally advanced or metastatic, non-resectable disease, which has progressed despite all standard therapies including CPI or for whom no standard or clinically acceptable therapy exists.
• Part 4 (expansion cohorts in combination with pembrolizumab, with or without chemotherapy): Subjects with melanoma (all types), HNSCC, G/GEA, RCC, TCC, NSCLC, or MSI-high, TMB-high, MMR-deficient tumors, with histologically confirmed, locally advanced or metastatic, non resectable disease, which is either CPI-naive (melanoma, HNSCC, NPC) or progressed despite all standard therapies including CPI (NSCLC, RCC, TCC, uveal melanoma, MSI-high, TMB-high, or MMR-deficient solid tumors) or for whom no standard or clinically acceptable therapy exists.
• For Cohort F3 (NSCLC), subjects may have progressed on no more than 2 lines of standard therapy that must include at least one PD-1/L1 regimen.
• For Cohort F4 (HNSCC and NPC), subjects may be previously treated with no more than 1 prior chemotherapy regimen in metastatic setting. Prior PD-1/L1 in curative (neo-adjuvant/adjuvant) setting is allowed only if completed >/= 6 months prior to progression to local recurrence or metastatic disease.
• For Cohort F8, subjects must have previously untreated, histologically confirmed Stage II, IIIA or IIIB (T3-4N2) NSCLC. Lymph node disease requires histologic confirmation, while T3 disease requires only radiographic documentation. Subjects need to be able to undergo planned surgery.
• All subjects with non-squamous NSCLC must have documentation of absence of tumor activating EGFR mutations and absence of ALK gene rearrangements.
• PD-L1 by IHC (22C3): Parts 1 and 3: IHC optional. Part 2: IHC result mandatory but any score allowed. Combined Positive Score (CPS) ≥ 1% (or Tumor Proportion Score ≥50% for NSCLC; for TMB-high tumors, any TPS% is allowed). Part 4: Combined Positive Score (CPS) ≥ 1% (or Tumor Proportion Score ≥50% for NSCLC; for TMB-high tumors, any TPS% is allowed). For Cohort F8, any TPS (including 0%) is acceptable.
• Adequate hematologic, coagulation, hepatic and renal function and ECOG score as defined per protocol.

Select Exclusion Criteria:

• Prior exposure to OX40 agonists. Exposure to anti-PD-1 and/or anti PD-L2 CPIs or an agent targeting other co-stimulatory T-cell receptor pathways.
• Receipt of any investigational product or any approved anticancer drug(s) or biological product(s) within 4 weeks prior to the first dose of study drug with certain exceptions.
• Hematologic malignancies (e.g., ALL, AML, MDS, CLL, CML, NHL, Hodgkin's lymphoma and multiple myeloma)
• Prior or concurrent malignancies. Exception: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of INBRX-106.
• Grade ≥ 3 immune-related adverse events (irAEs) or irAE that lead to discontinuation of prior immunotherapy. Some exceptions as defined per protocol apply.
• Active autoimmune disease or documented history of autoimmune disease that required systemic steroids or other immunosuppressive medications. Certain exceptions as defined in protocol apply.
• Diagnosis of immunodeficiency or treatment with systemic immunosuppressive medications within 7 days prior to the first dose of study drug. Certain exceptions as defined in protocol apply.
• History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection. Exceptions as defined in protocol apply.
• Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids or other immunosuppressive medications.
• Clinically significant cardiac condition, including myocardial infarction, uncontrolled angina, viral myocarditis, cerebrovascular accident, or other acute uncontrolled heart disease < 3 months prior to enrollment on this trial; left ventricular ejection fraction (LVEF) < 50%; New York Heart Association (NYHA) Class III or IV congestive heart failure; or uncontrolled hypertension; or oxygen saturation <92% on room air.
• Active, hemodynamically significant pulmonary embolism within 12 weeks prior to enrollment on this trial.
• Major surgery within 4 weeks prior to enrollment on this trial.
• Anti-infectious drug treatments (i.e., antibiotics) within 4 weeks prior to the first dose of study drug.
• Prior organ allograft transplantations or allogeneic peripheral blood stem cell (PBSC) or bone marrow (BM) transplantation.
• Additional in- and exclusion criteria per protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 30 centers

• City of Hope — Duarte
• Los Angeles Cancer Network — Glendale
• California Research Institute — Los Angeles
• Valkyrie Clinical Trials — Los Angeles
• Valkyrie Clinical Trials — Murrieta
• Providence Medical Foundation — Santa Rosa
• Clermont Oncology Center — Clermont
• Mid Florida Hematology and Oncology Center — Orange City
• … and 22 more centers

Taiwan · 5 centers

• Changhua Christian Hospital (CCH) — Changhua
• E-Da Cancer Hospital — Kaohsiung City
• Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH) — Kaohsiung City
• National Cheng Kung University Hospital — Tainan
• Taipei Veterans General Hospital — Taipei

South Korea · 4 centers

• The Catholic University of Korea, St. Vincent's Hospital — Gyeonggi-do
• Asan Medical Center — Seoul
• Severance Hospital, Yonsei University Health System — Seoul
• The Catholic University of Korea Seoul St. Mary's Hospital, — Seoul

Singapore · 3 centers

• Curie Oncology — Singapore
• Icon Cancer Centre Farrer Park — Singapore
• Icon Cancer Centre Mount Alvernia — Singapore

Publications

• Holay N, Yadav R, Ahn SJ, Kasiewicz MJ, Polovina A, Rolig AS, Staebler T, Becklund B, Simons ND, Koguchi Y, Eckelman BP, de Durana YD, Redmond WL. INBRX-106: a hexavalent OX40 agonist that drives superior antitumor responses via optimized receptor clustering. J Immunother Cancer. 2025 May 21;13(5):e011524. doi: 10.1136/jitc-2025-011524. PMID 40404202

Identifiers

NCT: NCT04198766 · Ph 1 Ph 2 INBRX-106 · KEYNOTE A99 and MK-3475-A99

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗