| 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) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.1 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| 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 |
|
| 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 |
|
| 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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects may be included if:
1. Willing and able to give written, and dated, informed consent (or 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 (in the Investigator’s opinion), and be accessible for follow-up
3. Subjects diagnosed with Ph+ CML-CP, Ph+ CML-AP, Ph+ CML-BP, or Ph+ ALL (with at least 1 pathology report within 3 months before Screening) who are refractory or intolerant to at least 3 TKIs or are not eligible (e.g.: due to comorbidities, hypersensitivity to excipients, outside of the US – 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. Minimum life expectancy of at least 3 months in the Investigator’s opinion
7. Adequate organ and immune system function as indicated by the following laboratory values obtained ≤ 2 weeks prior to IMP administration:
- ANC ≥ 1000/mm3 applies only to subjects diagnosed with CML-Chronic phase
- Platelets ≥ 50,000/mm3 applies only to subjects diagnosed with CML-Chronic phase
- Serum creatinine ≤ 2.0 mg/dL OR calculated creatinine clearance > 60 mL/min (based on the Cockroft-Gault formula)
- Total bilirubin ≤ 1.5 mg/dL or ≤ 2 mg/dL (for liver metastases)
- AST ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN (for liver metastases)
- ALT ≤ 2.5 × ULN or ≤ 5 × ULN (for liver metastases)
- Alkaline phosphatase ≤ 5 × ULN (unless bone metastases are present)
- Prothrombin time < 1.5 × ULN
8. Subjects of childbearing potential must practice an acceptable method of birth control as judged by the Investigator:
a. Medically acceptable methods of birth control include the use of either a contraceptive implant or a contraceptive injection (e.g., Depo-Provera™) or an IUD, same sex partner, a vasectomized partner, or an oral contraceptive taken continually within the past 3 months and the subject has to agree to continued use during the study
b. To adopt another birth control method, or a double-barrier method which consists of a combination of any 2 of the following: diaphragm, cervical cap, condom, or a spermicide at least 2 months prior to study entry and must continue to use contraception for the duration of the study
c. Subjects who are postmenopausal for at least 1 year as per Investigator’s discretion or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy has been performed on the subject)
9. 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 protocol and judged by the Investigator for the duration of the study and for 3 months after the last IMP administration
10. Female subjects of childbearing potential must have a negative serum pregnancy test
11. Female subjects should be non-lactating |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if:
1. Any major surgery, as determined by the Investigator, within 4 weeks of IMP administration
2. Inability to swallow oral medication
3. Inability to undergo venipuncture and/or tolerate venous access
4. Evidence of organ dysfunction or any clinically relevant deviation from normal in physical examination, ECG findings, vital signs, or clinical laboratory test findings as per the Investigator’s discretion
5. Positive exclusion tests: urine pregnancy tests (if applicable), HIV, hepatitis B surface antigen, or hepatitis C virus
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. Received an investigational agent within 30 days (or for investigational agents with long half-life a washout of 5 half-lives will be required) of IMP administration or intake of an investigational drug during the course of this study
8. 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
9. Use of concomitant medication that might reasonably influence the results of the study prior to IMP administration and at any time during the study
10. Known or suspected history of significant drug abuse as judged by the Investigator
11. History of alcohol abuse or excessive intake of alcohol, defined as regular weekly intake of more than 8 units of alcohol in females or 15 units of alcohol in males (Note: 1 unit equals 25 mL spirits, 125 mL wine, or 250 mL beer or lager) in the 12 months prior to study entry
12. Inability or unwillingness to comply with study procedures, restrictions, and requirements, as judged by the Investigator
13. Involvement in the planning and/or conduct of the study (applies to Sponsor, Contract Research Organizations, and study center staff, etc.)
14. Had cytotoxic chemotherapy or radiotherapy within 21 days (or 42 days for nitrosoureas or mitomycin C) or targeted therapy such as but not limited to BCR-ABL Tyrosine Kinase Inhibitors ≤ 14 days prior to the first IMP administration visit, or those who have not recovered (greater than Grade 1 by NCI CTCAE v4.03) from AEs due to agents administered more than 28 days earlier than the first IMP administration visit, with the exception of alopecia
15. Malabsorption syndrome or other illness that could affect oral absorption of the IMP
16. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
17. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
a. Uncontrolled hypertension (diastolic blood pressure > 85 mmHg; systolic blood pressure > 145 mmHg)
b. Recent (< 1 year) history of myocardial infarction (MI), unstable angina, coronary heart disease, cerebrovascular accident, or transient ischemic attack (TIA)
c. Congestive heart failure (New York Heart Association [NYHA] Class III or IV) within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than 30% within 6 months prior to the Screening visit
d. History of clinically significant (as determined by the treating physician) arrhythmia
e. Prolonged rate corrected QT interval ( QTcF) on the Screening ECG (> 470 msec)
18. Uncontrolled intercurrent illness including, but not limited to the following: ongoing or active infection, uncontrolled seizure disorder, psychiatric or social circumstances that would limit compliance with study requirements as per the Investigator’s discretion
19. Subjects who are eligible and willing to undergo transplant will be excluded
20. Autologous or allogeneic stem cell transplant ≤ 3 months (90 days) prior to Screening; any evidence of ongoing graft versus host disease (GVHD) or GVHD requiring immunosuppressive therapy ≤ 28 days prior to the first IMP administration visit
21. Another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ)
22. Any condition or illness that, in the opinion of the Investigator, would compromise subject safety or interfere with the evaluation of the safety of the drug
23. Intake of any restricted medications as described in the study restrictions
24. Any contraindications for repeated bone marrow sample collection |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| throghout the study duration |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint will be:
• 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
|
|
| 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.
The above sampling scheme may be modified (or reduced) when more information is available from the Part A study. |
|
| 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 (or RP2D) in patients |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Czech Republic |
| France |
| India |
| Italy |
| Korea, Republic of |
| Poland |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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