IRB Study Number 24-549
Status Recruiting
Institute Taussig Cancer Institute
Description
2.1.1. Primary Objectives
• To assess the safety and tolerability and determine the maximum-tolerated dose (MTD) and/or the RP2D of INBRX-106 as a single agent administered as an IV infusion in adult subjects with locally advanced or metastatic solid tumors.
• To assess the safety and tolerability and determine the MTD and/or the RP2D of INBRX-106 in combination with pembrolizumab administered as an IV infusion in adult subjects with locally advanced or metastatic solid tumors.
• To assess the safety and tolerability of INBRX-106 in combination with pembrolizumab and chemotherapy regimens in adult subjects with locally advanced or metastatic NSCLC.
• To assess the antitumor activity of INBRX-106 in combination with pembrolizumab. (Part 4 Cohorts F3 and F4)
2.1.2. Secondary Objectives
• To assess the PK of INBRX-106 as a single agent and in combination with pembrolizumab with or without chemotherapy.
• To assess the immunogenicity of INBRX-106 as a single agent and in combination with pembrolizumab with or without chemotherapy.
• To assess the preliminary antitumor activity of INBRX-106 as a single agent and in combination with pembrolizumab with or without chemotherapy. (All cohorts except F3 and F4)
Inclusion Criteria
Males or females aged ≥18 years on day of signing informed consent.
Tumor types included:
• Part 2 Cohort C3 (single-agent expansion cohorts): Subjects with NSCLC with histologically confirmed, locally advanced or metastatic, nonresectable disease, which has progressed despite all standard therapies including CPI or for whom no
standard or clinically acceptable therapy exists. A minimum of 4 subjects must be willing to provide paired fresh tumor biopsies at screening and on treatment.
• Part 4 (pembrolizumab combination expansion cohorts):
− Cohort F3: NSCLC with histologically confirmed, locally advanced or metastatic disease, which has progressed on no more than 2 lines of standard therapy that must include at least one PD-1/L1-regimen.
− Cohort F4: CPI naïve subjects with:
o histologically confirmed HNSCC (non-nasopharyngeal) (Cohort F4c).
o histologically confirmed nasopharyngeal carcinoma (Cohort F4d).
− Note: Cohort F4 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.
− Note: for Cohort F4c, a minimum of 4 subjects is required to provide paired fresh biopsies.
− Cohort F7: histologically confirmed, locally advanced or metastatic NSCLC.
- PD-L1 IHC (22C3) test result:
• Existing PD-L1 IHC test results with the monoclonal antibody clone 22C3 will be accepted.
• Prior PD-L1 IHC test result or tissue availability are required for enrollment. Central confirmation of PD-L1 test results will be performed retrospectively when possible.
− Cohort C3: PD-L1 IHC TPS ≥50% is mandatory for enrollment with the exception of subjects with TMB-high status (≥10 mut/mb, as confirmed by a Clinical Laboratory Improvement Amendments [CLIA]-certified, FDA-approved assay), for whom any TPS is allowed.
− Cohort F3: PD-L1 IHC TPS ≥50% is mandatory for enrollment with the exception of subjects with TMB-high status (≥10 mut/mb as confirmed by a CLIA-certified, FDA-approved assay); for those, any TPS is allowed.
− Cohort F4: PD-L1 IHC combined positive score (CPS) ≥1% is mandatory for enrollment.
− Cohort F7: Any TPS (including 0%) is acceptable for enrollment.
− All cohorts: Subjects without available PD-L1 IHC test results with antibody clone 22C3 whose initial archival tissue sample was PD-L1 “negative” need to provide formalin-fixed archival tissue for central testing. If archival tissue is unavailable, a fresh biopsy is required. For subjects in Cohorts C3 and F4c, the fresh pre-treatment paired biopsy can be used for PD-L1 for enrollment.
For Part 4 Cohort F3, subjects must be refractory or relapsed to PD-1 or PD-L1 CPI monoclonal antibodies (or anti-CTLA4 CPI monoclonal antibodies, in which these CPIs are FDA approved) administered either as monotherapy or in combination with other CPIs or other therapies.
Measurable disease as defined by RECIST v1.1.
• Note: Tumor lesions that are situated in a previously irradiated (or other locally treated) area will be considered measurable, provided that there has been clear imaging-based progression of the lesions since the time of radiation.
- Adequate hematologic function, defined by the following:
• Absolute neutrophil count ≥1500 cells/μL.
• Platelet count ≥100,000/μL.
• Hemoglobin ≥9.0 g/dL. Transfusions are allowed at any time during the study.
- Adequate hepatic function, defined by all of the following:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 upper limit of normal (ULN), and total bilirubin ≤1.5 ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN (Exception: Subjects who have serum bilirubin increases due to underlying Gilbert’s Syndrome or familial benign unconjugated hyperbilirubinemia).
- Adequate renal function defined as follows:
• creatinine clearance ≥30 mL/min for Cohorts C3, F3, and F4.
• creatinine clearance (or glomerular filtration rate) ≥50 mL/min for Cohort F7.
- Coagulation tests, defined by the following:
• Activated partial thromboplastin time (aPTT) ≤1.5 × ULN.
• International normalized ratio (INR) ≤2.0. Exception: INR 2 to ≤3 is acceptable for subjects on anticoagulants.
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
Estimated life expectancy, in the judgment of the Investigator, of at least 12 weeks.
Male and female subjects of childbearing potential must be willing to completely abstain or agree to use a highly effective method of contraception (ie, less than 1% failure rate), from the time of signing informed consent and for the duration of study participation through 4 months, following the last dose of study drug. See Appendix 2 for a list of some examples of highly effective contraception.
• A woman of childbearing potential is any woman, regardless of sexual orientation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (ie, has had menses at any time in the preceding 12 consecutive months).
• A man of childbearing potential is any man who has not been surgically sterilized (ie, has not undergone bilateral orchiectomy).
- Ability to understand and the willingness to sign a written informed consent document and comply with the study procedures.
Exclusion Criteria
- Prior exposure to OX40 agonists.
• Part 4 Cohort F4 prior exposure to anti-PD-1 and/or anti-PD-L1 CPIs in relapsed/metastatic setting.
- Receipt of any investigational product or any approved anticancer drug(s) or biological product(s) within 4 weeks (or 5 half-lives, whichever is shorter) prior to the first dose of study drug.
• Exceptions: Hormone replacement therapy, testosterone, androgen deprivation therapy for prostate cancer, endocrine therapy for breast cancer beyond progression, or oral contraceptives.
Receipt of radiotherapy within 2 weeks prior to the first dose of study drug. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation to non-CNS disease.
Allergy or sensitivity to INBRX-106 or known allergies to antibodies produced from Chinese hamster ovary cells, which in the opinion of the Investigator suggests an increased potential for an adverse hypersensitivity to INBRX-106.
• Cohorts F3, F4, and F7: Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Cohort F7: Any known hypersensitivity to chemotherapy agents (pemetrexed, carboplatin, cisplatin, paclitaxel, nab-paclitaxel) or hypersensitivity to folic acid or vitamin B12 (Cohorts F7a and F7b).
Hematologic malignancies (eg, acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and multiple myeloma).
For subjects with NSCLC:
• Cohorts F3 and F7: Received radiation therapy to the lung >30 Gy within 6 months prior to the first dose of study treatment.
• Cohorts F3 and F7: Subjects with non-squamous NSCLC with tumor activating EGFR mutations or ALK gene rearrangements.
• Cohorts F7a and F7b: Unable or unwilling to take folic acid or vitamin B12 supplementation.
• Cohorts F7a and F7b: Squamous histology. Mixed histology (eg, adeno-squamous) is allowed if the predominant type is non-squamous. If small cell elements are present, the subject will be excluded.
• Cohort F7c: Non-squamous histology. Mixed histology (eg, adeno-squamous) is allowed if the predominant type is squamous. If small cell elements are present, the subject will be excluded.
Has known active CNS metastases and/or carcinomatous meningitis. Participants 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 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. These cases must be reviewed and discussed with the Medical Monitor or Study Director for potential inclusion.
- Grade ≥3 irAEs or irAEs that led to discontinuation of prior immunotherapy.
• Exceptions: Hypothyroidism, Type 1 DM, adrenal insufficiency, and dermatologic irAEs (except previous Steven Johnson Syndrome, toxic epidermal necrolysis, or other severe forms of dermatitis) are allowed. Type 1 DM should be controlled with reduction of toxicity to Grade 1 or less.
- Active autoimmune disease or documented history of autoimmune disease that required systemic steroids or other immunosuppressive medications, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, Wegener’s, Sjögren’s syndrome, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, autoimmune hepatitis, vasculitis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, and glomerulonephritis.
• Exception: Endocrinopathies managed with hormone replacement therapy are allowed (eg, hypothyroidism, Type 1 DM, adrenal insufficiency).
- Diagnosis of immunodeficiency or treatment with systemic immunosuppressive medications within 7 days prior to the first dose of study drug.
• Exceptions: Daily prednisone equivalent ≤10 mg/day; topical, inhaled, or intranasal corticosteroids, and adrenal replacement steroid doses ≤7.5 mg/day prednisone equivalent are allowed.
Subjects who received granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or erythropoietin within 14 days prior to the first dose of the study drug.
History of hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection. Notes:
• If HBV and HCV test results are ≥6 months old or not available in the medical history, then this must be confirmed by baseline test results obtained during Screening. If HIV test results are ≥6 months old or not available in the medical history, then this must not be confirmed by baseline test results obtained during Screening.
• HIV-infected subjects in order to be eligible must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as 1) CD4+ T cell count >350 cells/mm3 at time of screening; 2) achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening; 3) on a stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1). Subjects with history of Kaposi sarcoma and/or multicentric Castleman's disease for HIV-positive subjects are excluded.
• Subjects with past or ongoing HCV infection will be eligible for the study if they completed their treatment at least 1 month prior to starting study intervention and have a negative HCV RNA test.
• Subjects with controlled hepatitis B will be eligible as long as they meet the following criteria: 1) Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Subjects on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study treatment; and 2) Subjects who are positive for anti-hepatitis B core antibody, negative for hepatitis B surface antigen, and negative or positive for anti-hepatitis B surface antibody, and who have an HBV viral load under 100 IU/mL, do not require HBV anti-viral prophylaxis.
Clinically significant cardiac condition, including myocardial infarction, uncontrolled angina, viral myocarditis, cerebrovascular accident, or other acute uncontrolled heart disease <3 months prior to the first dose of the study drug; left ventricular ejection fraction <50% New York Heart Association Class III or IV congestive heart failure; uncontrolled hypertension; or oxygen saturation <92% on room air.
Active interstitial lung disease or pneumonitis or a history of interstitial lung disease or pneumonitis requiring treatment with steroids or other immunosuppressive medications.
Active, hemodynamically significant pulmonary embolism within 12 weeks prior to the first dose of study drug.
Major surgery within 4 weeks prior to the first dose of the study drug.
Active infection that requires systemic therapy within 4 weeks prior to the first dose of study drug.
• Exception: Local viral or local fungal infections are permitted.
• Note: Antibiotic, anti-viral or anti-fungal prophylaxis in absence of active infection is allowed.
Pregnant or nursing females.
Prior organ allograft transplantations or allogeneic peripheral blood stem cell/bone marrow transplantation.
Live viral vaccine therapies within 4 weeks prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: Measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccines. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Any known, documented, or suspected history of illicit substance abuse that would preclude subject from participation, unless clinically justified (ie, will not interfere with study participation and/or will not compromise trial objectives) per judgment of the Investigator and with approval of the Medical Monitor or Study Director.
• Exception: Physician-prescribed medicinal opioids or cannabinoids are allowed for pain management. Cannabinoids are allowed in subjects from states that have legalized its use.
Any other disease or clinically significant abnormality in laboratory parameters, including serious medical or psychiatric illness/condition, which in the judgment of the Investigator might compromise the safety of the subject or integrity of the study, interfere with the subject participation in the trial, or compromise the trial objectives.
Has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier (this includes subjects with previous immunomodulatory therapy with residual immune-related AEs). Subjects receiving ongoing replacement hormone therapy for endocrine immune-related AEs will not be excluded from participation in this study. Inclusion of subjects with other non-clinically significant (Grade ≤2) toxicities should be discussed and approved by the Medical Monitor or Study Director.
• Note: In Cohort F7 (all sub-cohorts), subjects with severe (>Grade 2) pre-existing neurotoxicity are excluded. In Cohort F7b, subjects with pre-existing ototoxicity or hearing impairment are excluded.
- Squamous NSCLC subjects with ongoing hemoptysis or otherwise documented high risk of bleeding, atelectasis, hemothorax, or pneumothorax. Note: For any potential subjects with squamous NSCLC, their status and risk of bleeding should be discussed with the Study Director and/or Medical Monitor on a case-by-case basis.
