Study of DCC-3014 in Patients With Advanced Tumors and Tenosynovial Giant Cell Tumor

Study Overview
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Brief Summary
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This is a multicenter, open-label Phase 1/2 study of DCC-3014 in patients with malignant solid tumors and tenosynovial giant cell tumor (TGCT). There will be 2 distinct parts in this study: Dose Escalation (Phase 1) and Expansion (Phase 2). Phase 1 will enroll both malignant solid tumor and TGCT patients. Phase 2 will comprise two cohorts (Cohort A and Cohort B) and will only enroll TGCT patients.

Official Title
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A Multicenter Phase 1/2, Open-Label Study of DCC-3014 to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics in Patients With Advanced Tumors and Tenosynovial Giant Cell Tumor

Conditions
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Advanced Malignant Neoplasm, Pigmented Villonodular Synovitis, Giant Cell Tumor of Tendon Sheath, Tenosynovial Giant Cell Tumor, Tenosynovial Giant Cell Tumor, Diffuse

Intervention / Treatment
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* Drug: DCC-3014


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Dose Escalation Phase: Patients ≥18 years of age Patients must have: advanced malignant solid tumors; or symptomatic TGCT for which surgical resection is not an option (tumor biopsy to confirm diagnosis required if no histology/pathology available at screening) Malignant solid tumor patients only: Able to provide a tumor tissue sample Must have 1 measurable lesion according to RECIST Version 1.1 Malignant solid tumor patients only: Must have ECOG performance status of 0-1 Adequate organ and bone marrow function If a female of childbearing potential, must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures. Expansion Phase (Cohorts A and B) Patients ≥18 years of age Patients must have symptomatic TGCT for which surgical resection is not an option (tumor biopsy to confirm diagnosis required if no histology/pathology available at screening) a) Expansion Cohort B: patients must have prior systemic treatment with anti-CSF1 or anti-CSF1R therapy, with the exception of imatinib or nilotinib Adequate organ and bone marrow function Must have at least 1 measurable lesion according to RECIST Version 1.1 If a female of childbearing potential, must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures. Exclusion Criteria Dose Escalation Phase: Received anticancer therapy or therapy for TGCT, including investigational therapy, within 2 weeks or 28 days for therapies with half-life (t1/2) longer than 3 days prior to the administration of study drug. Unresolved toxicity (Grade >1 or baseline) from previous anticancer therapy or TGCT therapy, excluding alopecia. Known active CNS metastases. History or presence of clinically relevant cardiovascular abnormalities. Systemic arterial or venous thrombotic or embolic events. QT interval corrected by Fridericia's formula (QTcF) >450 ms in males or >470 ms in females or history of long QT syndrome. Left ventricular ejection fraction (LVEF) <50%. Concurrent treatment with proton-pump inhibitor(s). Major surgery within 2 weeks of the first dose of study drug. Malabsorption syndrome or other illness that could affect oral absorption. Known human immunodeficiency virus, active hepatitis B, active hepatitis C, or active mycobacterium tuberculosis infection. If female, the patient is pregnant or lactating. Known allergy or hypersensitivity to any component of the study drug. Any other clinically significant comorbidities. Expansion Phase (Cohorts A and B) Expansion Cohort A: received systemic therapy targeting CSF1 or CSF1R; previous therapy with imatinib and nilotinib is allowed. Expansion Cohort B: discontinued systemic therapy targeting anti-CSF1 or anti-CSF1R due to drug-induced liver injury. Treatment with therapy for TGCT, including investigational therapy, within 2 weeks or 28 days for therapies with a t1/2 longer than 3 days prior to the administration of the study drug. Known metastatic TGCT or other active cancer that requires concurrent treatment. QT interval corrected by Fridericia's formula (QTcF) >450 ms in males or >470 ms in females or history of long QT syndrome. Left ventricular ejection fraction (LVEF) <55%. Concurrent treatment with proton-pump inhibitor(s). Major surgery within 2 weeks of the first dose of study drug. Any clinically significant comorbidities Malabsorption syndrome or other illness that could affect oral absorption. Known human immunodeficiency virus (HIV), active or chronic hepatitis B, active or chronic hepatitis C, or active mycobacterium tuberculosis infection. If female, the patient is pregnant or lactating. Known allergy or hypersensitivity to any component of the study drug. Contraindication for MRI Active liver or biliary disease, including evidence of fatty liver, nonalcoholic steatohepatitis (NASH), or cirrhosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Experimental Treatment<br>Dose Escalation Phase: Increasing doses of DCC-3014 beginning at 10 mg QD for 28 day cycles until disease progression or unacceptable toxicity. Expansion Phase: Dosing of different patient cohorts at the dose level determined from the Dose Escalation Phase of the study. | Drug: DCC-3014<br>* CSF1R inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Identify the dose limiting toxicities for each dose level tested and determine the maximum tolerated dose and recommended Phase 2 dose | Day 1 - Day 28 of Cycle 1 for each dose level tested | 
| Incidence of Adverse Events | Identify the observed adverse events, serious adverse events associated with DCC-3014 | Cycle 1 through study completion (  24 months) | 
| Time to maximum observed concentration of DCC-3014 | Measure the time to maximum plasma concentration of DCC-3014 in patients | Cycle 1 Day 1 and Day 8, and Cycle 2 Day 1 (pre-dose and at multiple time points (up to 8 hours) post-dose) | 
| Maximum observed concentration of DCC-3014 | Measure the maximum observed concentration of DCC-3014 in patients | Cycle 1 Day 1 and Day 8, and Cycle 2 Day 1 (pre-dose and at multiple time points (up to 8 hours) post-dose) | 
| Trough observed concentration of DCC-3014 | Measure the observed trough concentration of DCC-3014 in patients | Cycle 1 Day 1 and Day 8, and Cycle 2 Day 1 (pre-dose and at multiple time points (up to 8 hours) post-dose) | 
| Area under the concentration-time curve of DCC-3014 | Measure the AUC of DCC-3014 | Cycle 1 Day 1 and Day 8, and Cycle 2 Day 1 (pre-dose and at multiple time points (up to 8 hours) post-dose) | 
| Half life of DCC-3014 | Measure half life of DCC-3014 in patients | Cycle 1 Day 1 and Day 8, and Cycle 2 Day 1 (pre-dose and at multiple time points (up to 8 hours) post-dose) | 
| Objective response rate (ORR= complete response [CR]+partial response [PR]) (Expansion Phase only) | Assessed by central read using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | At Week 25 (Cycle 7, Day 1) | 
| Duration of response rate (DOR) (Expansion Phase only) | Measure time from PR or CR to disease progression or death | Baseline through 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (Expansion Phase only) | Assessed by central read using tumor volume score and modified RECIST (mRECIST) Version 1.1 | At Week 25 (Cycle 7, Day 1) | 
| Range of Motion (ROM) (Expansion Phase only) | Measure mean change from baseline in relative ROM | Baseline to Week 25 (Cycle 7, Day 1) | 
| Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) Score (Expansion Phase only) | Proportion of responders based on Brief Pain Inventory (BPI) worst pain numeric rating scale (NRS) and narcotic analgesic use by Brief Pain Inventory-30 (BPI-30) | Baseline to Week 25 (Cycle 7, Day 1) | 
| Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Score (Expansion Phase only) | Analysis of patient reported outcomes based upon the patient-reported outcomes measurement information system (PROMIS) physical function questionnaire | Baseline to Week 25 (Cycle 7, Day 1) | 
| Worst Stiffness Numeric Rating Scale (NRS) Score (Expansion Phase only) | Analysis of patient reported outcomes based upon the Worst Stiffness Numeric Rating Scale (NRS) | Baseline to Week 25 (Cycle 7, Day 1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TGCT, DTGCT, PVNS