Modular Phase II Study to Link Targeted Therapy to Patients With Pathway Activated Tumors: Module 2 - Dovitinib for Patients With Tumor Pathway Activations Inhibited by Dovitinib Including Tumors With Mutations or Translocations of FGFR, PDGFR, VEGF, cKIT, FLT3, CSFR1, Trk and RET
Overview
- Phase
- Phase 2
- Intervention
- Dovitinib (TKI258)
- Conditions
- Tumor Pathway Activations Inhibited by Dovitinib
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 80
- Locations
- 49
- Primary Endpoint
- Clinical Benefit Rate (CBR)
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
The purpose of this signal seeking study was to determine whether treatment with dovitinib (TKI258) demonstrated sufficient efficacy in select pathway-activated solid tumors and/or hematologic malignancies to warrant further study.
Detailed Description
This was a phase II, open label study to determine the efficacy and safety of treatment with dovitinib (TKI258) in patients with a diagnosis of select solid tumors or hematological malignancies that have been pre-identified (prior to study consent) to have mutations, translocations or amplifications and whose disease has progressed on or after standard treatment. Genomic profiling is becoming more accessible to patients and their physicians. As such, more patients have been identified with potentially-actionable mutations, translocations or amplifications but do not have access to targeted drug treatment. This is a signal-seeking study to match patients with tumor pathway activations inhibited by dovitinib to the RTK inhibitor dovitinib. Pre-identification of mutations, translocations, or amplifications will be performed locally at a CLIA certified laboratory prior to participation on the trial. For the purpose of this study, genomic profiling is not considered part of screening. Informed consent must be signed before any screening activities take place. Once eligibility (screening criteria met) has been confirmed by Novartis, the patient will initiate therapy with dovitinib single-agent. The patient may not receive any additional anti-cancer therapy during treatment with dovitinib. Patients received study treatment until disease progression (assessed by investigator per RECIST 1.1 or appropriate hematologic response criteria), unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), otherwise known as End of Treatment. All patients who discontinue from study treatment due to disease progression must have their progression clearly documented. Disease assessment (by RECIST 1.1 or appropriate hematological response criteria) will be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), until disease progression or end of treatment, whichever occurs first. The frequency of disease assessment may be reduced to every 12 weeks for patients who have at least 4 post-baseline disease assessments and are clinically stable (except AML patients). Scans was assessed locally by the investigator. After discontinuation of treatment, patients, regardless of reason for treatment discontinuation, will be followed for safety for 30 days after the last dose. All patients will be followed for survival status every 3 months for 2 years after the last patient has enrolled in the study,regardless of treatment discontinuation reason (except if consent is withdrawn or patient is lost to follow-up)
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients eligible for inclusion in this study had to meet all of the following criteria:
- •Patient's age was ≥ 18 years of age at the time of signing informed consent.
- •Patient had a confirmed diagnosis of a selected solid tumor (except for primary diagnosis of urothelial tumors, hepatocellular carcinoma (HCC), endometrial carcinoma, metastatic breast cancer (mBC), squamous NSCLC, and renal cell carcinoma (RCC)) or hematologic malignancies (except for primary diagnosis of FLT3 AML and multiple myeloma). Additional tumor types could be excluded during the course of the study in the case of early futility or success based upon an interim analysis or at the discretion of Novartis.
- •Patient was in need of treatment because of progression or relapse defined as:
- •radiological progression for solid tumor and lymphoma
- •for hematologic malignancies, measureable progression or relapse by appropriate criteria
- •Patients had pre-identified tumor with a mutation and/or translocation of one of the known kinase targets of dovitinib. The qualifying alteration were assessed and reported by a CLIA-certified laboratory. The mutations included:
- •FGFR 1-3 (amplifications were also allowed)
- •PDGFRα or PDGFRβ
- •VEGFR1-2 (KDR)
Exclusion Criteria
- •Patients eligible for this study did not meet any of the following criteria:
- •Patients who received prior treatment with dovitinib (TKI258).
- •Patients with a known hypersensitivity to dovitinib (TKI258) or to its excipients.
- •Patients with brain metastasis or history of brain metastasis or leptomeningeal carcinomatosis.
- •Patients with diarrhea ≥ CTCAE grade
- •Patients with neuropathy ≥ CTCAE grade
- •Patients with acute or chronic pancreatitis.
- •Patients with external biliary drains.
- •Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) ≤ 6 months prior to starting study drug. Note: Patients with recent DVT who were treated with therapeutic anti-coagulant agents for at least 6 weeks are eligible.
- •Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:
Arms & Interventions
TKI258
Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Intervention: Dovitinib (TKI258)
Outcomes
Primary Outcomes
Clinical Benefit Rate (CBR)
Time Frame: Week 16
CBR determined by investigator assessment for each tumor assessment \& defined as responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) ≥ 16 wks. Confirmed CR/PR or SD prior to 16 wks,but discontinued prior to 16 wks for reasons other than progressive disease,will have their clinical benefit defined non-evaluable; confirmed CR/PR or SD prior to 16 wks,but progressed prior to 16 wks,will be considered not achieving clinical benefit;if CR/PR/SD occurred prior to 16 wks,but progressed at or after 16 wks without evidence of CR/PR/SD at or after 16 wks,will also be considered not achieving clinical benefit. CBR will be analyzed by comparing achieved CBR with a historical control rate of each tumor type,\& if there is at least 90% probability that the response rate in a tumor type exceeds the historical rate,then the tumor type will be considered a success. CBR: CR+PR+SD the assessment criteria was RECIST 1.1
Secondary Outcomes
- Progression-Free Survival (PFS)(36 months)
- Overall Survival (OS)(36 months)
- Overall Response (OR) of Partial Response (PR) or Greater(Week 16)