Clinical Trials Register

Summary
EudraCT Number:	2016-001754-18
Sponsor's Protocol Code Number:	CLR_15_03
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2016-001754-18

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to Determine Safety, Tolerability, Pharmacokinetics, and Activity of K0706 in Healthy Subjects and in Subjects with Chronic Myeloid Leukemia or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

A.4.1

Sponsor's protocol code number

CLR_15_03

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02629692

A.5.4

Other Identifiers

Name:

IND Number

Number:

127347

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sun Pharma Advanced Research Company (SPARC) Limited
B.1.3.4	Country	India
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Sun Pharma Advanced Research Company (SPARC) Limited
B.4.2	Country	India
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sun Pharma Advanced Research Company (SPARC) Limited
B.5.2	Functional name of contact point	Sponsor representative - Chimote
B.5.3	Address:
B.5.3.1	Street Address	17/B Mahal Industrial Estate, Mahakali Caves Road Andheri (E)
B.5.3.2	Town/ city	Mumbai
B.5.3.3	Post code	400 093
B.5.3.4	Country	India
B.5.4	Telephone number	+91 22 66455876
B.5.5	Fax number	+91 22 66455685
B.5.6	E-mail	geetanjali.chimote@sparcmail.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	K0706
D.3.2	Product code	K0706
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	K0706
D.3.9.2	Current sponsor code	K0706
D.3.9.3	Other descriptive name	K0706
D.3.9.4	EV Substance Code	SUB184023
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	48
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	K0706
D.3.2	Product code	K0706
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	K0706
D.3.9.2	Current sponsor code	K0706
D.3.9.3	Other descriptive name	K0706
D.3.9.4	EV Substance Code	SUB184023
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	24
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	K0706
D.3.2	Product code	K0706
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	K0706
D.3.9.2	Current sponsor code	K0706
D.3.9.3	Other descriptive name	K0706
D.3.9.4	EV Substance Code	SUB184023
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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

leukemia

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	21.0
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

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
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	21.0
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
• Evaluate the safety of K0706

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 and BP by hematologic outcomes who have failed ≥ 3 TKIs one of which includes ponatinib

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 selected BCR-ABL-associated hamatologic malignancies

The secondary objectives of Part C of the study are to evaluate:
• Anti-leukemic efficacy of K0706 by molecular outcomes
• Anti-leukemic efficacy of K0706 by hematological outcomes in CML-CP
• Anti-leukemic efficacy of K0706 by cytogenetic outcomes in CML-AP & BP
• Time to first hematologic response
• Duration of response
• Progression free survival (PFS) and Overall survival (OS)
• Population PK of K0706
• Safety of K0706 in the dosed subjects

E.2.3

Trial contains a sub-study

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 - inclusion of subjects needing legally acceptable representative/impartial witness will be in compliance to the enrolling country’s regulatory requirement) 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 must 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- inclusion of subjects needing legally acceptable representative/impartial witness will be in compliance to the enrolling country’s regulatory requirement) 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 Ph+CML CP, AP or BP who are resistant and/or intolerant to ≥ 3 prior TKIs one of which includes ponatinib. (Subjects with Ph+ ALL are not included)
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 must be non-lactating and non-breast-feeding

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 as per the Investigator’s discretion
6.Positive 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 any other investigational agent within 30 days or a washout of at least 5 half-lives, whichever is longer, of IMP administration
10.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
11.Known or suspected history of significant drug abuse as judged by the Investigator
12.Known or suspected history of alcohol abuse or excessive intake of alcohol in the 12 months prior to study entry
14.Radiotherapy or cytotoxic chemotherapy within 21 days or Vincristine within 7 days (for Ph+ ALL only); interferon or Cytarabine or immunotherapy within 14 days prior to the first IMP administration visit
15.Malabsorption syndrome or other illness that could affect oral absorption of the IMP
16.Clinically significant, uncontrolled, or active cardiovascular disease
17.Uncontrolled intercurrent illness
18.Subjects eligible and willing to undergo transplant
20.Autologous or allogeneic stem cell transplant ≤ 3 months prior to Screening
Other criteria may apply (refer to protocol)

Part C:
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
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 medication.
6.Positive 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 or a washout of at least 5 half-lives, whichever is longer of IMP administration
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 alcohol abuse or excessive intake of alcohol in the 12 months prior to study entry
12.Known or suspected history of significant drug abuse as judged by the Investigator
14.Radiotherapy or cytotoxic chemotherapy within 21 days or Vincristine within 7 days (for Ph+ ALL only); interferon or Cytarabine or immunotherapy within 14 days prior to the first IMP administration visit
15.Active central nervous system (CNS) disease as evidenced by cytology or pathology.
16.Malabsorption syndrome or other illness that could affect oral absorption of the IMP
18.Clinically significant, uncontrolled, or active cardiovascular disease
19.Uncontrolled intercurrent illness
20.Subjects eligible and willing to undergo bone marrow transplant
21.Autologous or allogeneic stem cell transplant ≤ 3 months prior to Screening
22.Another primary malignancy within the past 3 years or earlier.
23.Any contraindications for repeated bone marrow sample collection
24.Prior exposure to K0706 therapy as a participant in Part B of the protocol
Other criteria may apply (refer to protocol)

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
•Cohort A: For CML subjects in CP at study entry: Major Cytogenetic Response (MCyR), defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR).
CP subjects in CCyR are not eligible for this study.

•Cohort B: For CML subjects in AP at study entry: Major Hematologic Response (MaHR), defined as complete hematologic response (CHR) or no evidence of leukemia (NEL).
AP subjects in MaHR are not eligible for this study.

•Cohort C: For CML subjects in BP at study entry: MaHR, consisting of CHR or NEL. BP subjects in MaHR are not eligible for this study.

E.5.1.1

Timepoint(s) of evaluation of this end point

throghout the study duration

E.5.2

Secondary end point(s)

Part B:
• Anti-leukemic response assessment following the assessments following the hematological, cytogenetic and molecular assessments
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
- Cytogenetic response: Proportion of subjects who achieve CCyR
- Molecular responses: Proportion of subjects who achieve or maintain MMR
• In subjects with CML-AP or CML-BP
- Cytogenetic responses: Proportion of subjects who achieve CCyR, PCyR
- Molecular responses: Proportion of subjects who achieve 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

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

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

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised