E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009015 |
E.1.2 | Term | Chronic myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034877 |
E.1.2 | Term | Philadelphia chromosome positive |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of Part B of the study are to:
• Determine the MTD (or RP2D) of K0706 administered orally in subjects with the selected BCR-ABL-associated hematologic malignancies who have resistance or intolerance to the local Standard of Care CML therapy
• Evaluate the safety of K0706 in subjects with BCR-ABL-associated hematologic malignancies listed in the entry criteria
The primary objective of Part C of the study are to:
• Evaluate the anti-leukemic efficacy of K0706 in subjects with CML-CP by cytogenetic outcomes and in subjects with, AP, BP and Ph+ ALL by hematologic outcomes |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of Part B of the study are to:
• Evaluate the therapeutic activity of K0706
• Evaluate the PK of K0706 after multiple oral doses in subjects with the selected BCR-ABL-associated hematologic malignancies
The secondary objectives of Part C of the study are to evaluate:
• Anti-leukemic efficacy of K0706 by molecular outcomes
• Time to first hematologic response
• Duration of response
• Progression free survival (PFS) and Overall survival (OS)
• Population PK of K0706 with sparse sampling
• Safety of K0706 in the enrolled subjects |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part B:
1.Willing and able to give written/signed, and dated, informed consent (or by legally acceptable representative/impartial witness when applicable) and is available for the entire study
2.Willing and able to comply with the scheduled visits, treatment plan, laboratory testing, study procedures, and restrictions and be accessible for follow-up
3.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)
4.Male or female aged ≥ 18 years
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
6.Adequate organ and immune system function as indicated by the laboratory values obtained ≤ 2 weeks prior to IMP administration
7.Subjects of childbearing potential must practice a medically acceptable method of birth control as judged by the Investigator (refer to protocol for details)
8.Male subjects enrolled in the study should not father a child and are advised to prevent passage of semen to their sexual partner during intercourse using an acceptable method as detailed in the Inclusion criteria # 7 and judged by the Investigator for the duration of the study and for 3 months after the last IMP administration
9.Female subjects of childbearing potential must have a negative pregnancy test (as confirmed by a negative urine pregnancy test with a sensitivity of less than 50 mIU/mL or equivalent units of human chorionic gonadotropin).
10.Female subjects should be non-lactating and non-breast-feeding
Part C:
1.Willing and able to give written/signed, and dated, informed consent (or by legally acceptable representative/impartial witness when applicable) and is available for the entire study
2.Willing and able to comply with the scheduled visits, treatment plan, laboratory testing, study procedures, and restrictions, and be accessible for follow-up
3.Subjects with CML in any phase or Ph+ ALL who are resistant and/or intolerant to ≥ 3 prior TKIs or are not eligible for 3rd TKI [e.g.: due to comorbidities, hypersensitivity to excipients, resistance/intolerance to at least 2 TKIs other than imatinib) or the TKIs are ineffective against mutations detected in the patient’s tumor)]
4.Male or female aged ≥ 18 years
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
6.Adequate organ and immune system function as indicated by the following laboratory values obtained ≤ 2 weeks prior to IMP administration.
7.Subjects of childbearing potential must practice a medically acceptable method of birth control as judged by the Investigator (refer to protocol for details)
8.Male subjects enrolled in the study should not father a child and are advised to prevent passage of semen to their sexual partner during intercourse using an acceptable method as detailed in the Inclusion criteria # 7 and judged by the Investigator for the duration of the study and for 3 months after the last IMP administration
9.Female subjects of childbearing potential must have a negative pregnancy test (as confirmed by a negative urine pregnancy test with a sensitivity of less than 50 mIU/mL or equivalent units of human chorionic gonadotropin).
10.Female subjects should be non-lactating and non-breast-feeding |
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E.4 | Principal exclusion criteria |
Part B:
1.Presence of T315I mutations
2.Any major surgery, as determined by the Investigator, within 4 weeks of IMP administration
3.Inability to swallow oral medication
4.Inability to undergo venipuncture and/or tolerate venous access
5.Evidence of clinically significant organ dysfunction or any clinically relevant deviation from normal in physical examination, ECG findings, vital signs, or clinical laboratory test findings which in the opinion of the investigator may jeopardize the safety of the patient during the study or may interfere with the evaluation of the study drug
6.Positive exclusion tests: urine pregnancy tests (if applicable), HIV
7.History of any relevant allergy/hypersensitivity (including known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the IMP or its excipients)
8.Known history of active hepatitis B or hepatitis C
9.Received an investigational agent within 30 days of IMP administration
10.Sensitive substrates of CYP2C8 with a narrow therapeutic index, along with strong inhibitors or inducers of major CYP enzymes, should be avoided or used with caution in this trial
11.Use of concomitant medication that might influence the results of the study prior to IMP administration and/or anticipated need at any time during the study
12.Known or suspected history of significant drug abuse, of alcohol abuse or excessive intake of alcohol in the 12 months prior to study entry
13.Radiotherapy within 21 days or cytotoxic chemotherapy or Vincristine within 7 days (for Ph+ ALL only); interferon or Cytarabine or immunotherapy within 14 days prior to the first IMP administration visit Malabsorption syndrome or other illness that could affect oral absorption of the IMP
14.History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
15.Clinically significant, uncontrolled, or active cardiovascular disease
16.Uncontrolled intercurrent illness including
17.Subjects eligible and willing to undergo transplant
18.Autologous or allogeneic stem cell transplant ≤ 3 months prior to Screening
Part C:
1.Presence of T315I mutations
2.Any major surgery, as determined by the Investigator, within 14 days of IMP administration
3.Inability to swallow oral medication
4.Evidence of clinically significant organ dysfunction or any clinically relevant deviation from normal in physical examination, ECG findings, vital signs, or clinical laboratory test findings which in the opinion of the investigator may jeopardize the safety of the patient during the study or may interfere with the evaluation of the study medication.
5.Positive exclusion tests: urine pregnancy tests (if applicable), HIV
6.History of any relevant allergy/hypersensitivity (including known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the IMP or its excipients)
7.Known history of active hepatitis B or hepatitis C
8.Received an investigational agent within 30 days of IMP administration
9.Subjects on sensitive substrates of CYP2C8 with a narrow therapeutic index, or on strong inhibitors or inducers of major CYP enzymes, should be avoided or used with caution in this trial
10.Use of concomitant medication that might influence the results of the study prior to IMP administration/or anticipated need any time during the study
11.Known or suspected history of significant drug or alcohol abuse as judged by the Investigator
12.Radiotherapy within 21 days or cytotoxic chemotherapy or Vincristine within 7 days (for Ph+ ALL only); interferon or Cytarabine or immunotherapy within 14 days prior to the first IMP administration visit
13.Active central nervous system (CNS) disease as evidenced by cytology or pathology.
14.Malabsorption syndrome or other illness that could affect oral absorption of the IMP
15.Clinically significant, uncontrolled, or active cardiovascular disease
16.Uncontrolled intercurrent illness
17.Subjects eligible and willing to undergo bone marrow transplant
18.Autologous or allogeneic stem cell transplant ≤ 3 months prior to Screening
19.Another primary malignancy within the past 3 years or earlier.
20.Any contraindications for repeated bone marrow sample collection
21.Prior exposure to K0706 therapy as a participant in Part B of the protocol
Other criteria may apply (refer to protocol) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part B
The primary endpoint will be the MTD as determined by the frequency of DLTs
The safety endpoint will be AEs assessed based on the NCI CTCAE v4.03, ECOG performance status, vital signs, ECG, clinical laboratory values, and physical examination
Part C
In subjects with CML-CP:
- Major Cytogenetic Response (MCyR) rate (defined as the proportion of subjects who achieve a Complete Cytogenetic Response [CCyR]), or Partial Cytogenetic Response (PCyR) after the initiation of study treatment
- For subjects entering the study in MCyR, it is defined as the proportion of subjects who maintain the MCyR after initiation of study treatment upto 24 weeks on study treatment
In subjects with CML-AP or CML-BP or Ph+ALL
- Major Hematologic Response (MaHR) rate (defined as the proportion of subjects who achieve a Complete Hematologic Response [CHR]), or No Evidence of Leukemia (NEL) response after the initiation of treatment,
- For subject entering the study in MaHR, it is defined as the proportion of subjects who maintain the MaHR after initiation of study treatment upto 12 weeks on study treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
throghout the study duration |
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E.5.2 | Secondary end point(s) |
Part B:
• Anti-leukemic response assessment following the assessments outlined in the objectives above
The PK endpoints will be:
• Cmax, tmax, CL/F (for Cycle 2), AUC(0 tau), AUC(0 tau)/dose, Cmax/dose, Vz/F, and accumulation ratios for AUC and Cmax
• Ctrough
Part C:
• In subjects with CML-CP
- Hematological responses: Proportion of subjects who achieve or maintain complete hematological response
- Molecular responses: Proportion of subjects who achieve or maintain MMR
• In subjects with CML-AP or CML-BP or Ph+ALL
- Cytogenetic responses: Proportion of subjects who achieve CCyR, PCyR, confirmed MCyR
- Molecular responses: Proportion of subjects who achieve or maintain MMR
• In all subjects: Safety and tolerability in terms of incidence and severity of treatment emergent AEs
• In all subjects: Time to response, duration of response, PFS and OS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For efficacy outcome: throghout the study duration
For PK:
- Day 1 of Cycle 1: Predose, 0.5, 1, 2, 2.5, 4, 8, 24 hours (i.e., Day 2) postdose.
- Days 3, 8, 15, and 22 of Cycle 1: Predose only.
- Day 1 of Cycle 2 (Day 29 from start of treatment): Predose, 0.5, 1, 2, 2.5, 4, 8, 24 hours (i.e., Day 30) postdose.
- Days 8, 15, and 22 of Cycle 2: Predose only.
- Subsequent cycles: Predose samples on Day 1.
For Part C: throghout the study duration |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Part B: to determine the MTD/RP2D; Part C: to evaluate the anti-leukemic efficacy |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Germany |
Hungary |
India |
Italy |
Korea, Republic of |
Poland |
Romania |
Russian Federation |
Spain |
Thailand |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |