Gastrointestinal Stromal Tumor (GIST)
Conditions
Interventions
Trade Name: QINLOCK® (ripretinib)
Product Name: Ripretinib
Product Code: DCC-2618
Pharmaceutical Form: Tablet
INN or Proposed INN: RIPRETINIB
CAS Number: 1442472-39-0
Current Sponsor code: DCC-2618
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Sponsors
Deciphera Pharmaceuticals, LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Escalation Phase: 1. Participant must have at least progressed on imatinib or have documented intolerance to imatinib. There is no maximum number of prior treatments. 2. ECOG PS of 0 or 1 at Screening. 3. Adults =18 years of age with advanced GIST (unresectable or metastatic). 4. Histologic diagnosis of GIST and must be able to provide an archival tumor tissue sample taken after the last anti-cancer treatment, otherwise, a fresh tumor biopsy is required. 5. Must have at least 1 measurable target lesion according to mRECIST v1.1 (non-nodal lesions must be =1.0 cm in the long axis or = double the slice thickness in the long axis) within 21 days prior to the first dose of study drug. 6. Female participants of childbearing potential must have a negative serum beta-human chorionic gonadotrophin (ß-hCG) pregnancy test at screening and negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug. 7. Participants of reproductive potential must agree to use two methods of contraception with one of those methods being highly effective (See Protocol Section 8.3). 8. Adequate organ function and bone marrow reserve as indicated by the following laboratory assessments performed at screening: a. Absolute Neutrophil Count (ANC) =1000/µL b. Hemoglobin =8 g/dL c. Platelet count =75,000/µL d. Total bilirubin =1.5× the upper limit of normal (ULN) e. Aspartate transaminase (AST) and alanine transaminase (ALT) =3× ULN (or =5× ULN in the presence of hepatic metastases with approval of the medical monitor) f. Creatinine clearance =50 ml/min based on Cockcroft Gault estimation. g. Prothrombin time (PT), international normalized ratio (INR) and partial thromboplastin time (PTT) =1.5× ULN. Participants on a stable regimen of anticoagulant therapy for at least one month prior to the first dose of study drug may have PT/INR measurements >1.5× ULN if, in the opinion of the Investigator, the participant is suitable for the study after discussion with the medical monitor 9. Resolution of all toxicities from prior therapy to = Grade 1 (or participant baseline) within 1 week prior to the first dose of study drug (excluding alopecia). 10. Must be capable of understanding and complying with the protocol and the participant must have signed the informed consent form. A signed informed consent form (ICF) must be obtained before any study-specific procedures are performed. Expansion Phase: 1. Participant must have progressed on imatinib or have a documented intolerance to imatinib. Participants must be naïve to all other systemic GIST therapy, including ripretinib or imatinib combinations. 2. ECOG PS of 0 to 2 at Screening. 3. Adults =18 years of age with advanced GIST (unresectable or metastatic). 4. Histologic diagnosis of GIST and must be able to provide an archival tumor tissue sample taken after the last anti-cancer treatment, otherwise, a fresh tumor biopsy is required. 5. Must have at least 1 measurable target lesion according to mRECIST v1.1 (non-nodal lesions must be =1.0 cm in the long axis or = double the slice thickness in the long axis) within 21 days prior to the first dose of study drug. 6. Female participants of childbearing potential must have a negative serum beta-human chorionic gonadotrophin (ß-hCG) pregnancy test at screening and negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug. 7. Participants of reproductive potential must agree to use two methods of contraception with one of those methods being
Exclusion criteria
Exclusion criteria: Escalation Phase: 1.Received anti-GIST therapy within 14days or 5×the half-life(whichever is shorter) of the first dose of study drug (investigational or approved therapy). 2.Ongoing or prior participation in the DCC-2618-03-002 study 3.Prior therapy with ripretinib 4.Prior therapy with a MEK inhibitor 5.Participants with a prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial. For example, participants receiving adjuvant cancer treatment are not eligible if those medications are potentially active against the disease under study or excluded per protocol. NOTE: Participants with a history of breast cancer, requiring continued hormonal treatment (eg anti-estrogen or an aromatase inhibitor) may continue treatment. Participants with a history of prostate cancer, requiring continued support with luteinizing hormone-releasing hormone (LHRH) agonists, with or without androgens, may continue treatment. 6.Use of strong or moderate inducers of CYP3A (Flockhart, 2007), including certain herbal medications (eg, St.John’s Wort) within 14 days or 5× the half-life (whichever is longer) prior to the first dose of study drug through the end of treatment 7.Participant has known active central nervous system metastases 8.Participants with a history or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to CSR or RVO (ie, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, hyperviscosity or hypercoagulability syndromes) or other evidence of retinal pathology considered a risk factor for RVO or CSR. Glaucoma diagnosed within 1 month prior to Cycle1 Day1. 9.History of retinal degenerative disease 10.Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic reasons 11.Participants who have New York Heart Association Class II-IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, poorly controlled hypertension (defined as systolic >150 mmHg or diastolic blood pressure >90 mmHg), or congestive heart failure 12.Left ventricular ejection fraction (LVEF) <50% at screening 13.Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic attacks) or hemoptysis within 6 months before the first dose of study drug Expansion Phase: 1.Previous treatment with any other systemic GIST therapy other than imatinib. 2.Received imatinib treatment less than 10 days prior to the first dose of study drug. 3.Prior therapy with a MEK inhibitor. 4.Participants with a prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial. For example, participants receiving adjuvant cancer treatment are not eligible if those medications are potentially active against the disease under study or excluded per protocol. NOTE: Participants with a history of breast cancer, requiring continued hormonal treatment (e.g. anti-estrogen or an aromatase inhibitor) may continue treatment. Participants with a history of prostate cancer, requiring continued support with luteinizing hormone-releasing hormone (LHRH) agonists, with or without androgens, may continue treatment. 5.Use of stro
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Escalation Phase: 1. To evaluate safety and tolerability of ripretinib in combination with binimetinib in patients with advanced GIST. 2. To determine the RP2D and the maximum tolerated dose (MTD). The RP2D at or below the MTD will be declared based on safety and tolerability data and used for expansion. Expansion Phase: 1. To determine efficacy of the RP2D of ripretinib in combination with binimetinib as 2nd line therapy for patients with GIST by evaluating the objective response rate (ORR) according to GIST-specific modified RECIST (mRECIST v1.1). 2. To determine safety and tolerability of the RP2D of ripretinib in combination with binimetinib;Secondary Objective: Escalation Phase: 1. To characterize the pharmacokinetics (PK) of ripretinib and binimetinib when administered in combination. 2. To evaluate the efficacy of ripretinib in combination with binimetinib in advanced GIST. Expansion Phase: 1. To determine efficacy of the RP2D of ripretinib in combination with binimetinib as 2nd line therapy for patients with GIST including progression-free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), and time to response (TTR). 2. To characterize the PK of ripretinib and binimetinib when administered in combination at the RP2D.;Primary end point(s): Escalation Phase: The safety and tolerability of the combination of ripretinib and binimetinib will be evaluated by means of: • DLTs • Adverse event reports including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse event of special interest (AESI): squamous cell carcinoma (SCC) of skin Expansion Phase: Efficacy: ORR by mRECIST v1.1 based on investigator assessment Safety: Safety and tolerability will be evaluated by TEAEs, SAEs, AESIs.;Timepoint(s) of evaluation of this end point: The primary endpoint ORR is defined as the proportion of treated participants who achieved confirmed CR or confirmed PR per mRECIST v1.1. For t | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Escalation Phase: Secondary Pharmacokinetic Endpoints: Ripretinib and binimetinib pharmacokinetic endpoints will include the following but are not limited to: • Time to maximum observed concentration (tmax) • Maximum observed concentration (Cmax) • Trough observed concentration (Cmin) • Area under the concentration-time curve (AUC) Secondary Efficacy Endpoints: will be evaluated by mRECIST v1.1 and Choi criteria based on investigator assessment: • ORR (mRECIST v1.1) • PFS (mRECIST v1.1) • OS • ORR (Choi criteria) • DOR (mRECIST v1.1) • CBR at 4, 6, 9, 12 and 24 months (mRECIST v1.1) • TTR (mRECIST v1.1) Expansion Phase: Secondary Efficacy Endpoints: will be evaluated by mRECIST v1.1 and Choi criteria based on investigator assessment: • PFS (mRECIST v1.1) • OS • ORR (Choi) • DOR (mRECIST v1.1) • CBR (mRECIST v1.1) • TTR (mRECIST v1.1) Secondary Pharmacokinetic Endpoints: Ripretinib and binimetinib pharmacokinetic endpoints will include the following but are not limited to: • Time to maximum observed concentration (tmax) • Maximum observed concentration (Cmax) • Trough observed concentration (Cmin) • Area under the concentration-time curve (AUC);Timepoint(s) of evaluation of this end point: For timepoints see Protocol section 12.3.2.2. Analysis of the Secondary Endpoints | — |
Countries
Canada, Spain, United States
Contacts
Public Contactclinicaltrials@deciphera.com
Deciphera Pharmaceuticals, LLC
Outcome results
None listed