IRB Study Number 23-443
Status Recruiting
Institute Taussig Cancer Institute
Description
2.1.2. Part A2: KIN-2787 Plus Binimetinib Combination
• The primary objectives of Part A2 are to determine the safety and tolerability of oral administration of KIN-2787 + binimetinib including DLTs in participants with oncogenic BRAF mutation-positive advanced or metastatic solid tumors and melanoma harboring an NRAS mutation, and to identify the MTD and/or the appropriate dose for further clinical investigation.
• The secondary objective is characterization of PK properties of KIN-2787 and binimetinib in combination.
• Exploratory objectives include additional characterization of KIN-2787 PK, effect of KIN-2787 on survival, and other time-to-event endpoints, estimation of PD effects of KIN-2787 in blood samples and tumor biopsies, assessment of both genotype and genotypic changes under treatment to outcome.
2.2. Part B: Dose Expansion
• The primary objective of the Part B Dose Expansion portion of the study is to assess preliminary evidence of the anti-cancer activity of KIN-2787 in participants with advanced or metastatic solid cancers that harbor any oncogenic BRAF genomic alteration.
• The secondary objective is to further evaluate the safety, tolerability, and the PK characteristics of KIN-2787 at the RP2D.
• Exploratory objectives include additional characterization of KIN-2787 PK, effect of KIN-2787 on survival and other time-to-event endpoints, estimation of PD effects of KIN-2787 in blood samples and tumor biopsies, assessment of both genotype and genotypic changes under treatment to outcome, evaluation of the PK of a new KIN-2787 tablet formulation, impact on patient reported outcome (PRO) measures.
Inclusion Criteria
Participant has provided written informed consent prior to initiation of any study-specific procedures.
Men or women at least 18 years of age (or the legal age of majority per local regulations) at the time of signing the informed consent form (ICF).
Histologically or cytologically confirmed diagnosis of metastatic or advanced-stage malignancy, as follows:
• Part A – Any advanced or metastatic solid tumor
• Part B Cohort 1 and 2 – Unresectable and locally advanced (AJCC Stage III) or metastatic (AJCC Stage IV) NSCLC
• Part B Cohort 3 and 4 – Unresectable and locally advanced (AJCC Stage III) or metastatic (AJCC Stage IV) melanoma
• Part B Cohort 5 and 6 – Any unresectable and locally advanced (AJCC Stage III, or comparable Stage with other staging systems) or metastatic (AJCC Stage IV) solid tumor other than NSCLC or melanoma
• Part B Cohort 7 - Any unresectable and locally advanced (AJCC Stage III, or comparable Stage with other staging systems) or metastatic (AJCC Stage IV) solid tumor.
- Participants must have received prior locally approved standard of care appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
• In Part A, participants with specific cancers driven by BRAF Class I mutations, should have previously received a BRAF inhibitor- approved by the local regulatory agency (with or without an approved MEK inhibitor) containing therapy, where such treatment exists (hereafter referred to as "such treatment"). Additionally, such treatment must have resulted in clinical benefit, for example objective tumor shrinkage (i.e., complete response [CR] or partial response [PR]) or sustained disease control (e.g., continuous stable disease) or significant improvement in clinical symptoms, as determined by the treating physician. The following exceptions and clarifications to this criterion apply:
o If such treatment was medically contraindicated, then the participant may participate in this study.
o If, however, such treatment was administered as adjuvant treatment, then the requirement for treatment with an approved BRAF inhibitor does not apply, as this requirement was met by the adjuvant treatment.
Participant’s tumor (any type) harbors a BRAF mutation or is melanoma with an NRAS mutation identified by previous genomic analysis of tumor tissue or circulating tumor-derived (blood) nucleic acids (ctDNA) conducted in a CLIA-certified laboratory (in the US) or in accordance with local regulatory requirements (in other countries). Detailed descriptions of BRAF mutations are listed in Table 20 in Appendix A.
Willing to provide archived tumor tissue specimen (formalin-fixed paraffin embedded [FFPE] specimen) obtained within the last 5 years, if available.
Willing to undergo pre-treatment tumor biopsy, if medically feasible. The availability of a FFPE tumor biopsy specimen obtained within 2 months prior to consent from participants who have not received intervening systemic anti-cancer therapy will satisfy the pretreatment biopsy requirement.
Measurable (Part A and B) or evaluable (Part A only) disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix B).
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
An estimated life expectancy > 3 months in the opinion of the Investigator.
Corrected QT interval by Fredericia’s formula (QTcF) ≤ 470 msec (based on average of screening triplicates).
Adequate hematological lab assessments at screening, as follows:
• ANC ≥ 1.5 x 109 /L
• Platelets ≥ 75 x 109/L; for Part A2: ≥ 100 x 109/L without transfusion (at least 7 days since most recent blood transfusion)
• Hemoglobin ≥ 9.0 g/dL (at least 7 days since most recent blood transfusion)
- Adequate renal laboratory assessments, as follows:
• Serum creatinine ≤ 1.5 x ULN or estimated creatine clearance ≥ 50 mL/min as calculated using method standard for the institution
- Adequate hepatic laboratory assessments, as follows:
• Alanine aminotransferase (ALT) and AST ≤ 2.5 x ULN, or ≤ 5 x ULN in the presence of liver metastases.
• Serum total bilirubin ≤ 1.5 x ULN (< 2.0 x ULN for participants with documented Gilbert’s syndrome).
- Adequate coagulation laboratory assessments, as follows:
• Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x ULN, or international normalized ratio (INR) < 1.5 or within target range or < 3.0 if on prophylactic anticoagulation therapy.
- Able to swallow, retain, and absorb oral medications.
Specific Inclusion Criteria for Food Effect Assessment
Able to eat a standardized high fat, high-caloric meal within 30 minutes.
Able to fast for ≥ 10 hours.
Exclusion Criteria
- Participants who have received local therapy with either surgery and/or radiation therapy at least 4 weeks prior for whole brain radiation or 2 weeks prior for gamma knife, stereotactic radiation, or other localized radiotherapy to Cycle 1 Day 1 are eligible if they meet all of the following criteria:
• Residual neurological symptoms Grade ≤ 2
• On stable doses of corticosteroids (i.e., no increase in dose for preceding 14 days), if applicable
• Participants with asymptomatic untreated brain metastasis will be eligible if the treating physician determines that immediate CNS specific treatment is unlikely to be required and are evaluable using RANO – BM criteria.
This criterion has been removed as of Protocol Amendment 2.
In Part A, for participants with other solid tumors (other than NSCLC, melanoma, CRC, anaplastic thyroid cancer, and other solid tumors with approved BRAF Class I treatments) driven by BRAF Class I mutations, prior treatment with any approved or in-development small molecule BRAF-, MEK-, or MAPK-directed inhibitor therapy. This criterion will not be implemented until a decision to do so is made and communicated by the DRC.
In Part B, previous treatment with any approved or in-development small molecule BRAF-, MEK-, or MAPK-directed inhibitor therapy.
Myocardial infarction within 6 months of Cycle 1 Day 1, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina, or cardiac arrhythmia requiring medication except for atrial fibrillation that is rate controlled with medication.
Gastrointestinal tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis).
Active infection requiring IV antibiotics within 1 week of Cycle 1 Day 1.
Active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) Hepatitis B virus (HBV), Hepatitis C virus (HCV), and known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS)-related illness. The following circumstances apply:
a) Corona virus disease (COVID)-19/severe acute respiratory syndrome corona virus 2 (SARS-CoV2): This protocol excludes participants with active infections, as noted above. While SARS-CoV2 testing is not mandated for entry into this protocol, testing should follow local clinical practice standards. If a participant has a positive test result for SARSCoV2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV2, he/she is excluded.
b) HIV: Seropositivity can be confirmed per local regulations, however the following considerations apply in equivocal cases:
i. Participants whose viral load is negative, or HIV serology is negative may be eligible upon consultation with Sponsor. HIV seropositive participants who are otherwise healthy and at low risk for AIDS-related outcomes could be considered eligible.
ii. Potential eligibility for a specific HIV-positive protocol candidate should be evaluated and discussed with the Sponsor prior to any screening. HIV infected participants must be on anti-retroviral therapy (ART) and have well-controlled HIV infection/disease defined as:
▪ a CD4+ T cell count > 350 cells/mm3 at time of screening
▪ achieved and maintained a viral suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the available assay at the time of screening and for at least 12 weeks prior to screening Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1)
iii. The potential for drug-drug interactions will be taken into consideration.
iv. For participants in China and Japan, those who are confirmed HIV antibody positive are excluded.
c) HBV/HCV: Relevant laboratory tests should be performed at Screening. Refer to Centers for Disease Control (CDC) website: (https://www.cdc.gov/hepatitis/index.htm) for further details.
d) HBV: Participants who are Hepatitis B surface antigen positive are eligible if they have received hepatitis B virus (HBV) anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to enrollment. Participants should remain on anti-viral therapy throughout study intervention. For participants in China, Japan, and Taiwan when either Hepatitis B surface antibody (HBsAb) or Hepatitis B antibody (HBcAb) positive, the HBV deoxyribonucleic acid (DNA) must be < 200 IU/ml or 1000 copies/mL to be eligible under this criterion.
e) HCV: Participants with a history of Hepatitis C (HCV) infection are eligible if HCV viral load is undetectable at screening and have completed curative anti-viral therapy at least 4 weeks prior to enrollment.
- Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to NCI CTCAE version 5.0 Grade 0 or 1, or to levels otherwise dictated in the eligibility criteria with the exception of alopecia.
Exceptions:
a) Grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for > 6 months), such as ifosfamide-related proteinuria, may be allowed if they are not otherwise described in the exclusion criteria and there is agreement to allow study participation by both the Investigator and Sponsor.
b) Prior immune-related AEs (irAEs) except for endocrinopathies that are medically managed.
Systemic anti-cancer therapy with the exception of check point inhibitors within 21 days or 5 half-lives (whichever is shorter) prior to Cycle 1 Day1; systemic anti-cancer therapy with a checkpoint inhibitor within 30 days prior to Cycle 1, Day 1. Concurrent use of hormone deprivation therapy for castrate-resistant prostate cancer or for maintenance of postmenopausal status in breast cancer is permitted.
Therapeutic or palliative radiation therapy (outside of the central nervous system [CNS]) within 14 days of Cycle 1 Day 1.
Use of strong inhibitors or inducers of CYP3A, including grapefruit/grapefruit related citrus fruits (e.g., Seville oranges and pomelos) and any herbal medicine (e.g., St. John’s wort) within 1 week of Cycle 1 Day 1. Use of such substances during the study is prohibited.
Use of proton pump inhibitors, e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole within 7 days of Cycle 1 Day 1 and planned use during the study is prohibited.
Major surgery within 28 days of Cycle 1 Day 1.
Men and women of childbearing potential (WOCBP) who are unwilling to practice acceptable methods of effective birth control while on study through 30 days (women) (180 days for WOCBP in France) or 90 days (men) after receiving the last dose of study drug. Acceptable contraception is defined in Section 4.3.1. A WOCBP is a female who 1) has achieved menarche at some point 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (has had at least menses at any time preceding 12 consecutive months).
Women who are lactating/breast feeding or who plan to breastfeed while on study through 30 days after receiving the last dose of study drug.
Women with a positive serum pregnancy test or who are planning to become pregnant while on study (defined for this purpose as extending through 30 days) (180 days for participants in France) after receiving the last dose of study drug).
Known sensitivity to any of the products to be administered during dosing.
History of Noonan’s syndrome or other RASopathy syndromes.
Blood pressure ≥ 150/100 mmHg that cannot be controlled despite optimal medical therapy.
Inability to give written informed consent and/or to comply with all required study procedures and visits, in the opinion of the Investigator.
Participants with any other active treated malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix, Bowen’s disease. Participants with prostate intraepithelial neoplasm and ≤ 6 Gleason grade prostate cancer may also be considered. Participants with a history of other curatively treated cancers must be reviewed by the Sponsor prior to entering the study.
Part A2 KIN-2787 + Binimetinib Combination- Specific Exclusion Criteria
History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
History of allogeneic bone marrow transplantation or organ transplantation.
Left ventricular ejection fraction < 50% or institutional lower limit of normal (LLN).
