Chronic Myeloid Leukemia (for Part B and C), Healthy (For Part A)
Conditions
Keywords
CML, Chronic Myelogenous Leukemia, K0706, Vodobatinib, ponatinib-refractory/intolerant, treatment refractory chronic myeloid leukemia
Brief summary
Phase 1/2 study to determine safety, tolerability, pharmacokinetics, and anti-leukemic activity of Vodobatinib (K0706) in treatment-refractory/intolerant CML
Detailed description
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.
Interventions
DRUGVodobatinib (K0706) capsules
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.
Sponsors
Sun Pharma Advanced Research Company Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Part B and C: Single arm (Open-label) Part A: 2 arms: Investigational agent arm and Placebo arm (Double-blind).
Intervention 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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Examination of the Safety and Tolerability of Single Oral Doses of K0706 | Approximately 56 ± 2 days | Number of Participants with Adverse Events in Part A |
| To Determine the Maximum Tolerated Dose (MTD) as Determined by Frequency of Dose Limiting Toxicities | Dose Limiting toxicities observed over a 4 week period | PART B |
| Incidence and Severity of Treatment Emergent AEs (PART B) | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | Number of Participants with treatment emergent Adverse Events in Part B |
| For CML Subjects in CP at Study Entry | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | 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 |
| For CML Subjects in AP at Study Entry | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | 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 |
| For CML Subjects in BP at Study Entry | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Characterize the Pharmacokinetics (Cmax) of K0706 After Single Oral Doses in Healthy Male Subjects | Approximately 28 ± 2 days | Part A |
| To Characterize the Pharmacokinetics of K0706 (Cmax) After Single Oral Doses in Fasted and Fed State in Healthy Male Subjects | Approximately 28 ± 2 days | Part A |
| Pharmacokinetic Profile of K0706 - Cmax [The Maximum (Peak) Observed Drug Concentration After Dose Administration] | All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706) | PART B |
| Pharmacokinetic Profile of Vodobatinib (K0706) - Tmax [The Time to Reach Maximum (Peak) Drug Concentration After Dose Administration] | All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706) | PART B |
| Pharmacokinetic Profile of Vodobatinib (K0706) - AUC[0-tau] (AUC Over the Dosing Interval of 0-24 Hours). | All subjects will be followed for up to approximately 60 months after the first dose of Vodobatinib (K0706) | PART B |
| In Subjects With CML- CP:Proportion of Subjects Achieving Complete Hematological Response 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) | PART C |
| In Subjects With CML- CP:Proportion of Subjects Achieving Complete Cytogenetic Response 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) | PART C |
| 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) | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | PART C |
| In Subjects With CML-AP & BP: Proportion of Subjects Achieving Complete Cytogenetic Response 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) | PART C |
| In Subjects With CML-AP & BP: Proportion of Subjects Achieving Partial Cytogenetic Response (PCyR) as Assessed by Conventional Karyotyping of Bone Marrow Aspirate | All subjects will be followed up for 60 months from the first dose of K0706 | Part C |
| 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) | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | PART C |
| 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 | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | PART C; Time to response was calculated as time from date of first dose to date of first occurrence of best response |
| 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 | All subjects will be followed up for 60 months from the first dose of Vodobatinib (K0706) | PART C; Time to response was calculated as time from date of first dose to date of first occurrence of best response |
| In All Subjects Progression Free Survival (PFS) | 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. | PART C |
| In All Subjects Overall Survival (OS) | 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. | PART C |
| Incidence and Severity of Treatment Emergent AEs (PART C) | 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. | Number of Participants with treatment emergent Adverse Events in Part C |
| To Characterize the Pharmacokinetics (AUC(0-inf)) of K0706 After Single Oral Doses in Healthy Male Subjects | Approximately 28 ± 2 days | Part A |
| To Characterize the Pharmacokinetics of K0706 (AUC(0-inf)) After Single Oral Doses in Fasted and Fed State in Healthy Male Subjects | Approximately 28 ± 2 days | Part A |
Countries
Belgium, France, Hungary, India, Italy, Romania, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Part A comprised of 40 healthy subjects, Part B comprised of 61 patients and Part C comprised of 23 patients.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical Age <=18 years | 0 Participants |
| Age, Categorical Age >=65 years | 26 Participants |
| Age, Categorical Age Between 18 and 65 years | 98 Participants |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 102 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Race American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Race Asian | 0 Participants |
| Race (NIH/OMB) Race Black or African American | 13 Participants |
| Race (NIH/OMB) Race More than one race | 0 Participants |
| Race (NIH/OMB) Race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Race Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Race White | 55 Participants |
| Region of Enrollment Belgium | 0 participants |
| Region of Enrollment France | 0 participants |
| Region of Enrollment Hungary | 0 participants |
| Region of Enrollment India | 20 participants |
| Region of Enrollment Italy | 0 participants |
| Region of Enrollment Romania | 0 participants |
| Region of Enrollment South Korea | 0 participants |
| Region of Enrollment Spain | 4 participants |
| Region of Enrollment United Kingdom | 6 participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 1 | 0 / 1 | 1 / 6 | 0 / 7 | 0 / 3 | 1 / 7 | 1 / 15 | 1 / 6 | 0 / 3 | 1 / 12 | 0 / 1 | 3 / 22 |
| other Total, other adverse events | 1 / 6 | 3 / 6 | 4 / 6 | 2 / 6 | 4 / 8 | 3 / 8 | 1 / 1 | 1 / 1 | 6 / 6 | 7 / 7 | 3 / 3 | 7 / 7 | 13 / 15 | 6 / 6 | 3 / 3 | 10 / 12 | 1 / 1 | 20 / 22 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 1 | 0 / 1 | 2 / 6 | 3 / 7 | 0 / 3 | 4 / 7 | 3 / 15 | 4 / 6 | 3 / 3 | 2 / 12 | 0 / 1 | 6 / 22 |
Outcome results
None listed