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

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

Detailed Description
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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 is ongoing for the enrolled subjects.

Official Title
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A Two-Part Phase 1/2 Study to Determine Safety, Tolerability, Pharmacokinetics, and Activity of K0706, a Novel Tyrosine Kinase Inhibitor (TKI), in Healthy Subjects and in Subjects With Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

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

Intervention / Treatment
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* Drug: Vodobatinib (K0706) capsules


Participation Criteria
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Eligibility Criteria
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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 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 (Part C). Exclusion Criteria: Presence of T315I (PART C) 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

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: Single Group Assignment
Interventional Model Description: Part A: Single ascending dose in healthy volunteers. Part B: Multiple ascending dose safety and tolerability study in subjects with CML or Ph + ALL. Part C: Efficacy and safety study in subjects with treatment-resistant CML
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vodobatinib (K0706) capsules<br> | Drug: Vodobatinib (K0706) capsules<br>* Part A: 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the Maximum Tolerated Dose (MTD) as determined by frequency of Dose Limiting Toxicities | PART B | Dose Limiting toxicities observed over a 4 week period | 
| Incidence and severity of treatment emergent AEs as assessed by CTCAE v4.03 | PART B | 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 | 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 | 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 | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile of K0706 - Cmax [The maximum (peak) observed drug concentration after dose administration] | PART B and PART C | 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 and PART C | All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706) | 
| Pharmacokinetic profile of Vodobatinib (K0706) - Cmin [ Minimum observed drug concentration after dose administration] | PART B and PART C | 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 | 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 | 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 | 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 | 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 | 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 | 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 subjects who achieved MCyR | PART C | 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 subjects who achieved MMR | PART C | 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 | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | 
| In all subjects Overall survival (OS) | PART C | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | 
| Incidence and severity of treatment emergent AEs as assessed by CTCAE v5.0 | PART C | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, Chronic Myelogenous Leukemia, K0706, Vodobatinib, ponatinib-refractory/intolerant, treatment refractory chronic myeloid leukemia, Ponatinib