IRB Study Number 24-863
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To evaluate the safety profile of IDE196
• To evaluate the safety profile of IDE196 in combination with binimetinib
• To evaluate the safety profile of IDE196 in combination with crizotinib
• To identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D)
• To characterize the pharmacokinetic (PK) profile of IDE196 administered as powder-incapsule (PIC) or tablet as monotherapy, in combination with binimetinib, or in combination with crizotinib (Phase 1 [dose escalation], monotherapy and combination with binimetinib or crizotinib, and PK substudy)
• To characterize the PK profile of binimetinib and crizotinib administered in combination with IDE196
• To evaluate the anti-tumor activity of IDE196 monotherapy, in combination with binimetinib, and in combination with crizotinib, as determined by Investigator (INV) response assessment in the expansion cohorts.
Secondary Objectives
• To evaluate the anti-tumor activity of IDE196 monotherapy, in combination with binimetinib, and in combination with crizotinib, as determined by Investigator (INV) response assessment in the expansion cohorts.
• To evaluate the anti-tumor activity of IDE196 monotherapy, in combination with binimetinib, and in combination with crizotinib, as determined by INV response assessment in the expansion cohorts by prior treatment status (pretreated or treatment naïve)
Inclusion Criteria
5.1.1 General inclusion criteria
Patient must meet all of the following inclusion criteria prior to and on C1D1:
• Patient must be at least 18 years of age.
• Patient is able to provide written, informed consent before initiation of any study-related procedures, and is able, in the opinion of the Investigator, to comply with all the requirements of the study.
• Patient Population
̶ Diagnosis of one of the following:
o MUM: Metastatic uveal melanoma with histological or cytological confirmed metastatic disease. Metastatic disease may be treatment naïve* or have progressed (radiologically or clinically) on or after most recent therapy. If the most recent therapy was an immune-oncology agent, progressive disease must be confirmed**. Or o Non-MUM: Locally advanced and unresectable or metastatic non-uveal melanoma (eg, cutaneous or mucosal melanoma), CRC, or other solid tumor that has either progressed following prior standard therapies or that has no satisfactory alternative therapies and has evidence of GNAQ/11 hotspot mutation (codons Q209 or R183) by local testing in a CAP/CLIAcertified laboratory. If the most recent therapy was an immune-oncology agent, progressive disease must be confirmed**
*To be considered treatment naïve, Patients must not have had prior systemic therapies, liver directed therapies, ablations, or external beam radiation in the advanced or metastatic setting. Surgical resections in the metastatic setting are allowed. Prior neoadjuvant and adjuvant therapies are allowed as long as no treatments were given after diagnosis of metastatic disease. If a patient is treatment naïve and HLA-A*02:01 positive***, documentation is required to provide rationale why treatment with tebentafusp is not the ideal first-line treatment approach or of the patient’s intolerance to tebentafusp. **Confirmation of progressive disease (PD) following immune-oncology therapy is demonstrated with a second, successive imaging evaluation showing PD, ideally performed 4-8 weeks after the initial determination of PD. To be enrolled in the crizotinib monotherapy cohort the patient must meet all crizotinib-specific eligibility criteria and must have been treated with at least one prior liver-directed or systemic therapy in the metastatic setting. ***To be enrolled in the HLA-A*02:01 positive cohort, HLA status must be documented by testing in a CAP/CLIA-certified laboratory.
• Representative archival metastatic tumor specimens in paraffin blocks with an associated pathology report or a minimum of 15 formalin-fixed paraffin embedded (FFPE) slides is mandatory. If archival tissue block is exhausted or not available, then a tissue biopsy FFPE sample is required unless a biopsy is not medically feasible. Only tissue from a surgical resection or a core needle, punch, or excisional/incisional biopsy sample collection will be accepted. Fine needle aspiration (FNA) samples are not acceptable.
• Patients with a prior history of or clinically stable concurrent malignancy are eligible for enrollment provided the malignancy is clinically insignificant, no treatment is required, and the patient is clinically stable.
̶ Patients with a history of squamous or basal cell carcinoma of the skin or carcinoma in the situ of the cervix may be enrolled.
̶ Patients with prostate cancer with an elevated prostate-specific antigen (PSA) not requiring treatment may be enrolled.
• Measurable disease per RECIST v1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT or MRI scan (see additional comments in Section 5.1.2 for cutaneous melanoma patients). An enlarged lymph node must be ≥ 15 mm in short axis to be a measurable lesion.
̶ Lesions in previously irradiated areas should not be considered target lesions unless they have clearly progressed since radiotherapy.
̶ Liver lesions that received liver-directed therapies should not be considered target lesions unless they have clearly progressed since the therapy.
̶ For patients with metastases in the liver, these patients should have contrastenhanced liver imaging modality preference determined by expertise at the treating institution. Contraindications for imaging with contrast should be discussed and agreed to with the Medical Monitor prior to eligibility assessment.
• Patient has Eastern Cooperative Oncology Group (ECOG) performance status 0 – 1, and an anticipated life expectancy > 3 months
̶ Grade 2 or higher, moderate to severe, or rapidly increasing ascites to be discussed with the Medical Monitor prior to enrollment.
̶ Factors that predict potential for rapid progression and limited survival should be discussed with the medical monitor for overall potential risk/benefit of study participation (such factors include rapid progression on most recent imaging, LDH>1000, >50% liver involvement, inflammatory phenotype [sinus tachycardia, elevated WBC count, elevated platelet count]).
• Patient has adequate organ function at screening:
̶ Absolute neutrophil count ≥ 1500/mm3 without the use of hematopoietic growth factors
̶ Platelet count ≥ 75,000/mm3 (must be at least 2 weeks post-platelet transfusion and not receiving platelet-stimulating agents)
̶ Hemoglobin ≥ 8.0 g/dL (must be at least 2 weeks post-red blood cell transfusion and not receiving erythropoietic-stimulating agents)
̶ Total & direct bilirubin ≤ 1.5 x the upper limit of normal (ULN). For patients with documented Gilbert’s disease, total bilirubin ≤ 3.0 mg/dL is allowed
̶ AST and ALT ≤ 3 x ULN in the absence of documented liver metastases; ≤ 5 x ULN in the presence of liver metastases.
̶ Serum albumin ≥ 3.0 g/dL. Patients with serum albumin between 2.8 and 3.0 g/dL or received albumin replacement within 2 weeks of planned C1D1 can be considered for eligibility in discussion with the Medical Monitor.
̶ Creatinine clearance ≥ 45 mL/min by Cockcroft-Gault equation [Appendix 9]. Patients with creatinine clearance between 30 and 45 mL/min can be considered for eligibility in discussion with the Medical Monitor.
̶ Prothrombin time/International Normalized Ratio (INR) or partial thromboplastin time test results at screening ≤ 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose for at least 4 weeks prior to the first dose of study drug).
• Prior to study Day 1 (first dose), the patient must be:
̶ at least 4 weeks or 5 half-lives (T½) after the most recent biologic (antibody-based) or immunotherapy, whichever is shorter
̶ at least 2 weeks or 5 T½ after any prior systemic chemotherapy (> 6 weeks from systemic nitrosourea and mitomycin C) or targeted small molecule therapy, whichever is shorter. Local administration of nitrosoureas (eg, liver-directed carmustine [BCNU]) will be at least 2 weeks or 5 T½, whichever is shorter.
̶ at least 1 week after topical or ophthalmologic chemotherapy
̶ For patients being treated with either the binimetinib or crizotinib combination, see additional prior therapy criteria in Sections 5.1.4, 5.2.2, and 5.2.3.
Contraceptive Requirements
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 90 days after the last dose of study intervention:
• Refrain from donating fresh unwashed semen
Plus, either:
̶ 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
̶ Must agree to use contraception/barrier as detailed below:
o Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method (see Appendix 15) of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant Female participants are eligible to participate if they are:
• A woman of non-childbearing potential (WONCBP) as defined in Appendix 15 OR
• A woman of childbearing potential (WOCBP)
− Not pregnant or breastfeeding,
− Has a negative serum human chorionic gonadotropin pregnancy test result within 3 days prior to the first study drug administration, and
− Is using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency (as described in Appendix 15), during the study intervention period and for at least 30 days after the last dose of IDE196 or binimetinib and 90 days after the last dose of crizotinib. Systemically acting hormonal contraceptives should always be combined with a barrier method (preferably male condom). In general, use of a second form of effective (or highly effective) contraception (see definitions and examples in Appendix 15) is recommended, for instance the addition of a barrier method used by either the female or the male partner. Notes: The Investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. 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.
5.1.2 Non-MUM additional inclusion criteria
Patients must have exhausted all standard treatments or have documented intolerance per the Investigator.
Patients with microsatellite instable – high (MSI-H)/mismatch repair deficient (dMMR) tumors whose tumors are refractory to immune checkpoint inhibitor therapy, or who cannot tolerate immune checkpoint inhibitor therapy due to autoimmune toxicity are eligible. Refractory to immune checkpoint inhibitor therapy is defined as lack of objective response or tumor progression following a minimum of 12 weeks of continuous treatment unless treatment was terminated due to toxicity. Archival metastatic tumor specimens in paraffin blocks with an associated pathology report or a minimum of 15 FFPE slides is mandatory. For non-MUM patients whose archival tumor tissue is exhausted, a biopsy tissue FFPE sample is required unless a biopsy is not medically feasible.
• Only tissue from a surgical resection or a core needle, punch, or excisional/incisional biopsy sample collection will be accepted. FNA samples are not acceptable.
• Histologically confirmed locally advanced and unresectable or metastatic melanoma − For cutaneous melanoma: Must be confirmed by color medical grade photographs with a ruler if skin lesions present.
• Patients whose only measurable disease is based upon digital photography with calipers and ruler for cutaneous lesions must be discussed with the Sponsor Medical Monitor
• Documented RAF/RAS wild-type status
Colorectal cancer:
• Histologically confirmed locally advanced and unresectable or metastatic adenocarcinoma originating from the colon or the rectum
• Documented RAF/RAS wild-type status
5.1.3 Binimetinib combination additional inclusion criteria
• Adequate cardiac function represented by left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO or multi-gated acquisition (MUGA) scan and above the institutional lower limit of normal (LLN)
• For the dose expansion cohort approximately 25% of patients enrolled should be treatment naïve in the metastatic setting (ie, no prior systemic or liver directed therapies allowed except for surgical resections, external beam radiation therapy, or percutaneous ablations)
5.1.4 Crizotinib combination additional inclusion criteria
• Any prior chemotherapy (or other therapies with resulting significant myelosuppression) or major surgeries must have been completed at least 4 weeks prior to initiation of crizotinib.
• Patients with preexisting peripheral neuropathy can be included in the study if it is Grade 1 or lower, prior to initiation of crizotinib.
5.1.5 Biopsy-eligible patients, MUM and non-MUM
• Accessible lesion(s) that permit a total of at least two biopsies (pretreatment and on-treatment) without unacceptable risk of a significant procedural complication. Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine needle aspirates, cell pellets from effusions or ascites, lavage samples, and bone biopsies are not permitted.
• If multiple lesions are available, it is preferable to obtain the on-treatment biopsy from the same lesion (or organ) as the pretreatment biopsy, if feasible.
• Biopsy from the same lesion (or organ) as the pretreatment biopsy, if feasible.
• If a pretreatment biopsy was performed as part of patient’s standard of care within 28 days of C1D1, the biopsy does not need to be repeated if it can be made available to the Sponsor.
• Monotherapy
̶ Target lesions considered for core needle biopsies should be deemed suitable for retrieval of a minimum of three, but ideally five, cores at a given time point (minimum diameter 18-gauge). Cores for fresh frozen and FFPE samples will be collected in an alternating manner (first core for frozen tissue, second core for FFPE, etc.).
̶ Alternatively, a minimum of two cores at a given time point with a 14-gauge needle is acceptable. Cores for fresh frozen and FFPE samples will be collected in an alternating manner (first core for frozen tissue, second core for FFPE, etc.).
• Combinations
− Target lesions considered for core needle biopsies should be deemed suitable for retrieval of five cores at a given time point (minimum diameter 18-gauge). Cores for fresh frozen and FFPE samples will be collected in an alternating manner (first core for frozen tissue, second core for FFPE, etc.). − Alternatively, a minimum of three cores at a given time point with a 14-gauge needle is acceptable. Cores for fresh frozen and FFPE samples will be collected in an alternating manner (first core for frozen tissue, second core for FFPE, etc.).
Exclusion Criteria
5.2.1 General exclusion criteria for Phase 1 and Phase 2
The presence of any of the following would exclude a patient from being eligible for the study: AND note that additional exclusions apply (and are listed after this section) specifically and separately for either combination treatment with binimetinib OR crizotinib.
• Previous treatment with a PKC inhibitor
• Known MSI-H/dMMR tumors who have not previously received immune checkpoint inhibitors will be excluded.
• Have AEs from prior anti-cancer therapy that have not resolved to Grade ≤ 1 except for alopecia, prior peripheral neuropathy, or anemia. Endocrinopathies resulting from previous immunotherapy are considered part of medical history and not an AE.
• Participants with known symptomatic brain metastases requiring supraphysiologic doses of systemic corticosteroids (unless required for other than the treatment of brain metastases) or anti-convulsant medication. Participants with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued supra physiologic doses of corticosteroid treatment for these metastases (unless required for other than the treatment of brain metastases) for at least 2 weeks and are neurologically stable for at least 4 weeks (requires magnetic resonance imaging [MRI] confirmation). Carcinomatous meningitis or leptomeningeal disease is exclusionary. Any question pertaining to this criterion should be discussed with the Sponsor Medical Monitor.
• Known acquired immunodeficiency syndrome (AIDS)-related illness: human immunodeficiency virus (HIV) seropositive patients who are healthy and low risk for AIDS related outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed with Sponsor Medical Monitor and will be based on current and past cluster of differentiation 4 (CD4) and T cell counts, history (if any) of AIDS defining conditions (eg, opportunistic infections), and status of HIV treatment. Also, the potential for drug-drug interactions should be taken into consideration.
• Active infection requiring ongoing therapy (except nail fungus).
• Positive tests for Hepatitis B surface antigen (hBsAg) with detected Hepatitis B virus (HBV) DNA or positive Hepatitis C antibody with detected Hepatitis C virus (HCV) RNA.
• Surgical procedures that require general anesthesia ≤ 5 days prior to first scheduled dose of IDE196; in all cases, the patient must be sufficiently recovered and stable before study drug administration.
• Prior gastrectomy or upper bowel removal or any other gastrointestinal disorder or defect eg, malabsorption disorder such as Crohn’s disease or ulcerative colitis, that would interfere with absorption of IDE196, binimetinib, or crizotinib. Any ongoing diarrhea requires discussion with the Sponsor Medical Monitor.
• Patients who received radiotherapy within 2 weeks of the first dose of study drug.
• Patients who are receiving treatment with medications that cannot be discontinued prior to study entry and that are considered to be any of the following (see Appendix 6):
− Antineoplastic therapies (not including palliative radiotherapy) or investigational therapies other than IDE196
− known risk for QT prolongation, except for the specific use of oral 5-HT3 Receptor Antagonists (eg, ondansetron) for the management of nausea and vomiting (note: intravenous formulations are prohibited)
− Narrow Therapeutic Index sensitive substrates of P-gp and BCRP
− known to be strong inducers or inhibitors of CYP3A4/5
− known to be substrates of CYP3A4/5 with a narrow therapeutic index
• Females who are pregnant or breastfeeding
• Women of childbearing potential must not be considering getting pregnant during the study.
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
− History or presence of ventricular tachyarrhythmia
− Presence of unstable atrial fibrillation (ventricular response > 100 BPM); patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria
− Angina pectoris or acute myocardial infarction ≤ 6 months prior to starting study drug
− Congestive heart failure requiring treatment. For New York Heart Association Class 1, inclusion can be considered with discussion and agreement with the Medical Monitor
− Other clinically significant heart disease (eg, uncontrolled arrhythmia or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen, symptomatic bradycardia)
− Patients with a drug eluting stent for cardiovascular purposes placed ≤ 2 months prior to starting study drug
− Corrected QT interval using Fridericia’s method (QTcF):
o Monotherapy and binimetinib combination arms: QTcF > 460 msec on baseline ECG (mean of baseline values). If electrolytes are abnormal, they may be corrected, and baseline ECGs should be repeated (Appendix 7). In addition, heart rate < 45 bpm.
o Crizotinib combination arm: QTcF > 450 msec on baseline ECG (mean of baseline values). If electrolytes are abnormal, they may be corrected, and baseline ECGs should be repeated (Appendix 7). In addition, patients with asymptomatic persistent heart rate < 55 bpm must be discussed with the Medical Monitor for inclusion.
o Note: For patients with a significantly prolonged QRS complex (> 110 msec) due to a bundle branch block or an intraventricular conduction delay, an “adjusted” QTcF for the QRS widening will be used to evaluate study eligibility.
“Adjusted QTcF” = measured QTcF – [measured QRS – 90 msec]
• For patients receiving IDE196 PIC or crizotinib: allergy to mammalian meat products or gelatin.
• Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the opinion of the Investigator, would make the patient inappropriate for entry into the study.
5.2.2 Binimetinib combination additional exclusion criteria
• Prior therapy with a MEK inhibitor (eg, binimetinib, trametinib, cobimetinib).
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); current evidence of serous retinopathy or retinal detachment (except if the retinal detachment was a result of the underlying cancer).
• History of interstitial lung disease.
• Concurrent neuromuscular disorder associated with elevated creatine phosphokinase (CPK) (also known as “creatine kinase,” or “CK”), such as inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy.
• Uncontrolled arterial hypertension despite medical treatment
• Known hypersensitivity or contraindication to any component of binimetinib or its excipients
5.2.3 Crizotinib combination additional exclusion criteria
• Prior therapy directly targeting ALK, MET, or ROS1
• Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.
• History of pneumonitis or interstitial lung disease, but not history of prior radiation pneumonitis.
− NOTE: Patients with prior Grade 1 pneumonitis (asymptomatic; clinical or diagnostic observations only; intervention not indicated) due to prior immunotherapy can be considered for inclusion after discussion and agreement with the Medical Monitor.
5.2.4 Crizotinib or Binimetinib combination additional exclusion criteria
• History of syncope (except due to an acute medical condition [eg, hemorrhage] that is not likely to reoccur and with permission of the medical monitor) within 6 months of cycle 1 day 1. Any history of potential syncope should be clarified and verified if possible. All patients with prior history of syncope should be discussed with the Medical Monitor.
• History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli.
Exceptions:
• Patients with deep vein thrombosis that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants. Incidental asymptomatic thrombi discovered upon screening may be discussed with the Sponsor Medical Monitor for inclusion.
• Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled. No waivers of inclusion or exclusion criteria will be granted by the Investigator and the Sponsor or its designee for any patient enrolled into the study.
5.2.5 PK Study with pravastatin additional exclusion criteria
• Taken any dose of any statin (eg, pravastatin, rosuvastatin, lovastatin) within 7 days prior to enrollment in the study and cannot refrain from them through Cycle 2 Day 1
• Taken any inhibitor of OATP1B1, OATP1B3, OATP2B1 (eg, telmisartan, darolutamide, atazanavir, and ritonavir) within 7 days prior to enrollment in the study and cannot refrain from them through Cycle 2 Day 1.
• Taken drugs that interfere with the absorption, metabolism or elimination of pravastatin (eg, cyclosporine, gemfibrozil, clarithromycin, colchicine, fibrates, darunavir/ritonavir, lopinavir/ritonavir, colestipol, cholestyramine, cimetidine) within 7 days prior to enrollment in the study and cannot refrain from them through Cycle 2 Day 1
• Any contraindication, eg, hypersensitivity, associated to the use of statins or hypersensitivity to any component of pravastatin
• Active liver disease or unexplained, persistent elevations of serum transaminases
