Safety and Anti-leukemic Activity of Vodobatinib (K0706) for Treatment of Ph+ CML Resistant/Intolerant to ≥3 Prior CML Therapies

Phase 2TerminatedNCT02629692

Sun Pharma Advanced Research Company Limited124 enrolled

Overview

Phase 1/2 study to determine safety, tolerability, pharmacokinetics, and anti-leukemic activity of Vodobatinib (K0706) in treatment-refractory/intolerant CML

Part A ( for Healthy volunteers) of the study is completed. Part B dose-escalation study is completed. Recruitment in dose expansion is completed. Part C study in subjects with treatment-resistant/intolerant CML is also completed.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

124

Conditions

Healthy (For Part A)Chronic Myeloid Leukemia (for Part B and C)

Interventions

Vodobatinib (K0706) capsulesDRUG

Part A: Oral Vodobatinib (K0706) capsules in single ascending doses. Part B: Oral Vodobatinib (K0706) capsules in multiple ascending doses, once daily. Part C: Oral Vodobatinib (K0706) capsules at recommended phase 2 dose of 174 mg, once daily.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Part A Inclusion Criteria: * Healthy males aged 18 to 55 years Part B Key Inclusion Criteria: * Subjects diagnosed with Ph+ CML-CP, Ph+ CML-AP, Ph+ CML-BP, or Ph+ ALL who are refractory or intolerant to at least 3 TKIs or are not eligible (e.g.: due to comorbidities, hypersensitivity to excipients, lack of insurance coverage) for their local country's regulatory approved and medically appropriate TKIs (e.g., a TKI that is effective against mutations in the patient's tumor). Part C Key Inclusion Criteria: * Subjects diagnosed with Ph+ CML-CP, Ph+ CML-AP, Ph+ CML-BP, who are resistant and/or intolerant to ≥ 3 prior TKIs one of which includes ponatinib (Subjects with Ph+ ALL are not included). Part B and C: Other Inclusion Criteria * Willing and able to give written, and dated, informed consent * Male or female aged ≥ 18 years * Willing and able to comply with the scheduled visits * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Part A Exclusion Criteria: * Any major surgery, as determined by the Investigator, within 4 weeks of IMP administration * Inability to undergo venipuncture and/or tolerate venous access * Positive exclusion tests: HIV, hepatitis B surface antigen, or hepatitis C virus * Known or suspected history of significant drug abuse as judged by the Investigator Part B and C Exclusion Criteria: * Presence of T315I * Any major surgery, as determined by the Investigator, within 4 weeks of IMP administration * Inability to undergo venipuncture and/or tolerate venous access * Positive exclusion tests: urine pregnancy tests (if applicable), HIV, hepatitis B surface antigen, or hepatitis C virus * Known or suspected history of significant drug abuse as judged by the Investigator * Received any other investigational agent within 30 days or a washout of at least 5 half-lives, whichever is longer of IMP administration * Subjects who are eligible for potentially curative therapy that is available, including hematopoietic stem cell transplant * Another primary malignancy within the past 3 years or earlier (except for adequately treated non-melanoma skin cancer or cervical cancer in situ

Locations (35)

Outcomes

Primary Outcomes

Examination of the Safety and Tolerability of Single Oral Doses of K0706

Number of Participants with Adverse Events in Part A

Time frame: Approximately 56 ± 2 days

To Determine the Maximum Tolerated Dose (MTD) as Determined by Frequency of Dose Limiting Toxicities

PART B

Time frame: Dose Limiting toxicities observed over a 4 week period

Incidence and Severity of Treatment Emergent AEs (PART B)

Number of Participants with treatment emergent Adverse Events in Part B

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

For CML Subjects in CP at Study Entry

PART C: Proportion of subjects achieving Major Cytogenetic Response \[ defined as complete cytogenetic response (CCyR; 0% Ph+metaphases) or partial cytogenetic response (PCyR; 1-35% Ph+ metaphases)\] as assessed by conventional Karyotyping of Bone marrow aspirate

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

For CML Subjects in AP at Study Entry

PART C: Proportion of subjects achieving Major Hematologic Response \[ defined as complete hematologic response (CHR) or no evidence of leukemia (NEL)\] as assessed by complete blood count of peripheral blood sample

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

For CML Subjects in BP at Study Entry

PART C: Proportion of subjects achieving Major Hematologic Response \[defined as complete hematologic response (CHR) or no evidence of leukemia (NEL)\] as assessed by complete blood count of peripheral blood sample

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

Data from ClinicalTrials.gov

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The Oncology Institute of Hope and Innovation, Innovative Clinical Research Institute

Downey, California, United States

UCLA Hematologic Malignancy Program

Los Angeles, California, United States

Mayo Clinic

Jacksonville, Florida, United States

Board of Regents of the University System of Georgia

Augusta, Georgia, United States

Memorial Sloan Kettering Cancer Center - MAIN

New York, New York, United States

Baylor University Medical Center

Dallas, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

Huntsman Cancer Institute University of Utah

Salt Lake City, Utah, United States

Cliniques Universitaires Saint-Luc

Brussels, Belgium

Institut Paoli Calmettes

Marseille, Bouches-du-Rhône, France

...and 25 more locations

Secondary Outcomes

To Characterize the Pharmacokinetics (Cmax) of K0706 After Single Oral Doses in Healthy Male Subjects

Part A

Time frame: Approximately 28 ± 2 days

To Characterize the Pharmacokinetics of K0706 (Cmax) After Single Oral Doses in Fasted and Fed State in Healthy Male Subjects

Part A

Time frame: Approximately 28 ± 2 days

Pharmacokinetic Profile of K0706 - Cmax [The Maximum (Peak) Observed Drug Concentration After Dose Administration]

PART B

Time frame: All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706)

Pharmacokinetic Profile of Vodobatinib (K0706) - Tmax [The Time to Reach Maximum (Peak) Drug Concentration After Dose Administration]

PART B

Time frame: All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706)

Pharmacokinetic Profile of Vodobatinib (K0706) - AUC[0-tau] (AUC Over the Dosing Interval of 0-24 Hours).

PART B

Time frame: All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706)

In Subjects With CML- CP:Proportion of Subjects Achieving Complete Hematological Response as Assessed by Complete Blood Count of Peripheral Blood Sample

PART C

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

In Subjects With CML- CP:Proportion of Subjects Achieving Complete Cytogenetic Response as Assessed by Conventional Karyotyping of Bone Marrow Aspirate

PART C

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

In Subjects With CML- CP:Proportion of Subjects Achieving Major Molecular Response as Assessed by BCR-ABL Transcript Levels (BCR-ABL1 Ratio of ≤ 0.1%) in Peripheral Blood Using PCR (Polymerase Chain Reaction)

PART C

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

In Subjects With CML-AP & BP: Proportion of Subjects Achieving Complete Cytogenetic Response as Assessed by Conventional Karyotyping of Bone Marrow Aspirate

PART C

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

In Subjects With CML-AP & BP: Proportion of Subjects Achieving Partial Cytogenetic Response (PCyR) as Assessed by Conventional Karyotyping of Bone Marrow Aspirate

Part C

Time frame: All subjects will be followed up for 60 months from the first dose of K0706

In Subjects With CML-AP & BP: Proportion of Subjects Achieving Major Molecular Response as Assessed by BCR-ABL Transcript Levels (BCR-ABL1 Ratio of ≤ 0.1%) in Peripheral Blood Using PCR (Polymerase Chain Reaction)

PART C

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

Time to Major Cytogenetic Response (MCyR): Time to MCyR is the Time From First Dose to First MCyR (0-35% Ph+ Metaphases); Computed Only for CML-CP Subjects Who Achieved MCyR

PART C; Time to response was calculated as time from date of first dose to date of first occurrence of best response

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

Time to Major Molecular Response : Time to MMR is the Time From First Dose to First MMR (BCR-ABL1 Ratio of ≤ 0.1%) Computed Only for CML-CP Subjects Who Achieved MMR

PART C; Time to response was calculated as time from date of first dose to date of first occurrence of best response

Time frame: All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706)

In All Subjects Progression Free Survival (PFS)

PART C

Time frame: All subjects will be followed up at 12, 24, 36 months from the first dose of K0706 and beyond, until intolerance, disease progression or subject withdrawal from the study.

In All Subjects Overall Survival (OS)

PART C

Time frame: All subjects will be followed up at 12, 24, 36 months from the first dose of K0706 and beyond, until intolerance, disease progression or subject withdrawal from the study.

Incidence and Severity of Treatment Emergent AEs (PART C)

Number of Participants with treatment emergent Adverse Events in Part C

Time frame: All subjects will be followed up for up to 60 months from the first dose of Vodobatinib (K0706), unless subject discontinues due to intolerance or progression of disease.

Pharmacokinetic Profile of K0706 - Cmax [The Maximum (Peak) Observed Drug Concentration After Dose Administration]

PART C

Time frame: All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706)

Pharmacokinetic Profile of Vodobatinib (K0706) - Tmax [The Time to Reach Maximum (Peak) Drug Concentration After Dose Administration]

PART C

Time frame: All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706)

To Characterize the Pharmacokinetics (AUC(0-inf)) of K0706 After Single Oral Doses in Healthy Male Subjects

Part A

Time frame: Approximately 28 ± 2 days

To Characterize the Pharmacokinetics of K0706 (AUC(0-inf)) After Single Oral Doses in Fasted and Fed State in Healthy Male Subjects

Part A

Time frame: Approximately 28 ± 2 days