IRB Study Number 24-279
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To identify the maximum tolerated dose (MTD) and/ or recommended Phase 2 dose (RP2D), and evaluate the safety, tolerability and dose-limiting toxicities (DLTs) of HC-7366 in combination with belzutifan in patients with locally advanced (inoperable) or metastatic RCC with predominantly clear cell histology irrespective of VHL gene mutation status (combination only).
Secondary Objectives
• To preliminarily assess the potential antitumor activity of HC-7366 in terms of response rate, disease stabilization, and survival outcomes by assessing:
Overall response rate (ORR) per RECIST v1.1
Duration of response (DOR; CR or PR) or stable disease
Time to Response (TTR)
Median progression free survival (PFS) and PFS at six months
Median overall survival (OS) and 1-yr OS
• To determine the plasma concentration and PK parameters of HC-7366 following single and multiple doses of HC-7366 alone or in combination with belzutifan administered to patients with locally advanced (inoperable) or metastatic RCC with predominantly clear cell histology, irrespective of VHL gene mutation status (PK parameters of both HC-7366 and belzutifan will be measured).
• To characterize HC-7366 monotherapy safety and efficacy in RCC patients within the same study as the combination of HC-7366 and belzutifan (specifically at the same centers and under the same inclusion and exclusion criteria) (Monotherapy only based on primary endpoints related to safety and tolerability outlined in sub-bullets 2-6).
Inclusion Criteria
Be age 18 years or older (male or female) at the time of consent and has read, understood, and provided written informed consent and, if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures.
Has histologically or cytologically confirmed diagnosis of locally advanced (inoperable) or metastatic RCC with a predominant clear cell component, irrespective of VHL gene mutation status per American Joint Committee on Cancer (AJCC) (8th Edition) (excluding patients that have any component of collecting duct or medullary histology); prior nephrectomy is not mandatory.
Patients with residual, but well-controlled endocrinopathy (e.g., hypothyroidism) are eligible.
Patients with progressive disease after receipt of at least 2 and no more than 5 prior lines of therapy for metastatic (stage IV) disease, including but not limited to VEGF-directed tyrosine kinase inhibitors (TKIs), high-dose IL-2, immune checkpoint inhibitors, or Mtor inhibitors alone or in combination.
a. Note: A line of therapy is considered complete once the patient has progressed following such treatment. If a treatment regimen is changed before disease progression due to toxicity, for example, this is still considered part of the same line of therapy. In addition, maintenance therapy [that is, therapy with a different drug or drugs given to conserve an existing response or stable disease before disease progression] is not considered an additional line of therapy.
b. Note: If previously treated with immune checkpoint inhibitors, at least 4 weeks must have elapsed since the last dose prior to first dose of study treatment, and toxicities resolved.
Has at least one measurable lesion as per RECIST 1.1.
Has no RCC tumor that requires immediate surgical intervention.
If reasonably accessible, patients have at least one biopsiable lesion at baseline. Biopsies in this clinical study will conform to American Society of Clinical Oncology’s Ethical Framework for Including Research Biopsies in Oncology Clinical Trials. Provided there are suitable and accessible lesions, no biopsy contraindications, minimal risk of complications and a positive informed decision, patients are willing to provide fresh tissue for biomarker analysis, and, based on the adequacy of the tissue sample quality, for assessment of biomarker status. Two biopsies are planned and highly encouraged: at baseline (within 30 days prior to study Day 1) and at Cycle 2/Day 1 (+7 days). Newly obtained biopsy specimens are preferred to archived samples and formalin-fixed, paraffin-embedded block specimens are preferred to slides. Biopsies should not be taken from target lesions.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Has adequate organ function as defined in the following table (Table 4). Specimens must be collected at screening and within 10 days prior to the start of study treatment.
Have not experienced >10% body weight loss in the previous 4 weeks.
Have life expectancy of 3 months or greater as determined by the treating physician.
A female patient is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
a. Is not a women of childbearing potential (WOCBP) OR
b. Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in Appendix 3 during the intervention period and for at least 90 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention.
o A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine test or 72 hours for serum test before the first dose of study intervention.
o If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the patient must be excluded from participation if the serum pregnancy result is positive.
o Additional requirements for pregnancy testing during and after study intervention are located in Appendix 2.
o The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
o Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
c. Female patients must agree not to breastfeed or donate ova starting at screening, and throughout the study treatment, and for 90 days after the final administration of study drug.
- Male patients are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study intervention:
a. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
b. Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 3]) as detailed below:
o Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom.
o Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
c. Male patient with pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or for the time their partner is breastfeeding throughout the study treatment and for 90 days after the final administration of study drug.
d. Must not donate sperm during the treatment period and for at least 90 days after the final administration of the study drug.
Exclusion Criteria
Has received prior treatment with belzutifan or another HIF-2α inhibitor.
Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤2 weeks before allocation.
Has received any type of systemic anticancer antibody (including investigational antibody) ≤4 weeks before allocation.
Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment (except inclusion criteria 2).
Has had history of major surgery < 3 weeks before allocation including that intended for tumor treatment. Note: Adequate wound healing after major surgery must be assessed clinically.
Has received prior radiotherapy within 2 weeks before allocation. Patients must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is required for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
Has a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor.
Has any of the following:
• A pulse oximeter reading <92% at rest, or
• Requires intermittent supplemental oxygen, or
• Requires chronic supplemental oxygen.
Has a history of interstitial lung disease, pneumonitis within 12 months prior to screening, or current pneumonitis.
Have clinically significant cardiovascular disease within 6 months from first dose of study drug administration, including but not limited to unstable angina, acute myocardial infarction, PTCA or CABG, cerebrovascular accident, transient ischemic event, pulmonary embolism, clinically significant, symptomatic or uncontrolled arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes), QTc prolongation to greater than 450 msec in males and 470 msec in females, or New York Heart Association Class III or IV heart failure. Medically controlled arrhythmia stable on medication is permitted.
Has known additional malignancy that is progressing or required active treatment within the past 5 years. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that has undergone potentially curative therapy, superficial bladder cancer, or in situ cervical cancer. Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years.
Has a history of or known active central nervous system metastases and/or carcinomatous meningitis. Note: Patients with previously treated brain metastases may participate provided they are radiologically stable (i.e., without evidence of disease progression) for at least 4 weeks (28 days) by repeat imaging (repeat imaging should be performed during study screening), clinically stable, have no evidence of new or enlarging brain metastases, and without requirement for steroid treatment for at least 14 days prior to the first dose of study intervention. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
Has moderate to severe hepatic impairment (Child-Pugh B or C).
Has a known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (HC-7366 or belzutifan).
Has a history of retinitis or photosensitive skin disorders including (but not limited to) erythema multiforme, atopic eczema, psoriasis, viral exanthemata, pemphigus, and dermatitis herpetiformis.
Has a history of clinically severe autoimmune disease, or history of organ transplant.
Is unable to swallow orally administered medication intact or has a history or current evidence of a gastrointestinal disorder (e.g., Inflammatory bowel disease, Crohn’s disease, ulcerative colitis, gastrectomy, partial bowel obstruction, malabsorption) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption and metabolism of oral medications.
Has overt or latent disorders of the exocrine pancreas (such as acute or chronic pancreatitis of any etiology) or chronic (including autoimmune) rheumatoid arthritis, lupus, scleroderma, Sjogren’s syndrome, and polyarteritis nodosa.
Has an active infection requiring therapy (includes but not limited to active tuberculosis and COVID-19 infection).
Has known human immunodeficiency virus (HIV) and/or hepatitis B or C infections or is known to be positive for hepatitis B surface antigen (HbsAg)/hepatitis B virus (HBV) deoxy ribonucleic acid (DNA) or hepatitis C antibody or ribonucleic acid (RNA). Active hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
Has not recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Patients with a ≤ Grade 2 neuropathy may be eligible.
Has received colony-stimulating factors (CSFs) (e.g., granulocyte-CSF [G-CSF], granulocyte monocyte-CSF [GM-CSF] or recombinant erythropoietin [EPO]) or transfusion within 28 days before study treatment initiation.
Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. Note: Topical preparations are acceptable.
Note: A current list of strong/moderate inducers of CYP3A4 can be found at the following website. The link from the FDA does not provide an all-inclusive list. The investigator must review locally approved product labels and use the best medical judgment. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
- Is currently receiving either strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of CYP3A4 that cannot be discontinued for the duration of the study. Note: Topical preparations are acceptable.
Note: A current list of strong/moderate inhibitors of CYP3A4 can be found at the following website. The link from the FDA does not provide an all-inclusive list. The investigator must review locally approved product labels and use the best medical judgment.
Has a history of or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, or interfere with the individual’s ability to cooperate with the requirements of the study such that it interferes with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
Has a known substance abuse disorder(s) that would interfere with informed consent or cooperation with the requirements of the study.
Is pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through 90 days after the final administration of the study drug.
Is a first-degree relative of the investigator, staff, or study sponsor.
