An open-label, multicenter, study of INC424 monotherapy or in combination with azacitidine for patients with post-myeloproliferative disorders (MPD) – AML or with CMML

• Register: German Clinical Trials Register
• Last refreshed on: 8 April 2024
• Main ID: DRKS00007802
• Date of registration: 24/02/2015
• Prospective Registration: Yes
• Primary sponsor: Universität Leipzig
• Public title: An open-label, multicenter, study of INC424 monotherapy or in combination with azacitidine for patients with post-myeloproliferative disorders (MPD) – AML or with CMML
• Scientific title: An open-label, multicenter, study of INC424 monotherapy or in combination with azacitidine for patients with post-myeloproliferative disorders (MPD) – AML or with CMML - JAKVIDA
• Date of first enrolment: 15/06/2015
• Target sample size: 40
• Recruitment status: Recruiting stopped after recruiting started
• URL: http://drks.de/search/en/trial/DRKS00007802
• Study type: interventional
• Study design: Allocation: N/A: single arm study; Masking: Open (masking not used); Control: Other; Assignment: single; Study design purpose: treatment
• Phase: 1-2

Countries of recruitment

Germany

Contacts

• Name: Dietger Niederwieser
• Affiliation: Universitätsklinikum AöRDepartment für Innere MedizinHämatologie, Internistische Onkologie und Hämostaseologie

• Name: Dietger Niederwieser
• Affiliation: Universitätsklinikum AöRDepartment für Innere MedizinHämatologie, Internistische Onkologie und Hämostaseologie

Key inclusion & exclusion criteria

Inclusion criteria: 1. Patients must be diagnosed with postmyeloproliferative AML according to the 2008 World Health Organization criteria (Appendix A), irrespective of JAK2 mutation status or diagnosed with CMML with a white-blood-cell count above 13×10? cells /L.
2. Patients must give written informed consent according to local guidelines prior to any screening procedures.
3. Patients must not be eligible for another ongoing INC424 clinical trial.
4. Male or female patients =18 years
5. Patients with adequate liver function defined as direct bilirubin = 2.0 x ULN, and ALT = 2.5 x ULN.
6. Patients with adequate renal function defined as serum creatinine
= 2 x ULN.
7. Patients with an Eastern Cooperative Oncology Group (ECOG) perfor-mance status of 0, 1, or 2 (Appendix A).
8. Women of childbearing potential must have had a negative serum preg-nancy test within 72 hours prior to the administration of study drug. They must agree to use effective contraceptive methods (doctors approved contraception) throughout the study and for 3 months following the date of the last dose of study medication. Female patients who are more than 2 years postmenopausal or have had a hysterectomy will not be consid-ered of childbearing potential. Males with female partner of childbearing potential must agree to use effective contraceptive methods (doctors ap-proved con-traception) throughout the study and should avoid fathering a child for 3 months fol-lowing the date of the last dose of study medica-tion. Adequate forms of contraception are double-barrier methods (con-doms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depot, or injectable contraceptives, intrauterine devices, and tubal ligation.
9. Patients must have recovered or stabilized sufficiently from adverse drug reactions associated with prior treatments before beginning treatment with INC424.
Exclusion criteria: 1. Any diagnosis of malignant disease within the previous 12 months (ex-cluding treated early stage squamous or basal cell carcinoma with no complications)
2. Impairment of gastrointestinal (GI) function or GI disease that may signifi-cantly alter the absorption of INC424 (e.g., ulcerative diseases, uncon-trolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
3. Hepatic tumors in the medical history
4. Patients with known active hepatitis A, B, C or who are HIV-positive.
5. Patients with coagulation parameters (PT, PTT) =1.5 x ULN.
6. Patients with known hypersensitivity to INC424 or to its excipients or known or suspected hypersensitivity to azacitidine or mannitol.
7. Patients with serious concomitant medical illness:
a. history of severe congestive heart failure [grade = 3 according to CTCAE] or
b. clinically unstable ischemia or
c. acute myocardial infarction in the previous six months or
d. pulmonary hypertension [grade > 3 according to CTCAE] or
e. severe cardiac arrythmias [grade > 3 according to CTCAE] or
f. chronic pulmonary diseases [grade > 3 according to CTCAE] or
g. uncontrolled hypertension or
h. uncontrolled diabetes or
i. uncontrolled severe infections [grade > 3 according to CTCAE] or
j. any other severe or uncontrolled medical illness
8. Psychiatric illness that would prevent granting of informed consent
9. Patients receiving ongoing treatment with another investigational medica-tion or having been treated with an investigational medication within 30 days of study drug treatment.
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until termination of gestation, con-firmed by a positive ßHCG laboratory test (> 5 mIU/mL).
11. Patients with any concurrent condition that, in the Investigator’s opinion, would jeopardize the safety of the patient or compliance with the protocol.

Age minimum: 18 Years
Age maximum: None
Gender: All

Health Condition(s) or Problem(s) studied

C93.1
C92.0

C93.1

Acute myeloblastic leukaemia [AML]

C92.0

Chronic myelomonocytic leukaemia

Intervention(s)

Group 1: The oral dose of 25 mg INC424 bid will be administered continuously until: disease progression; unacceptable toxicity; death; discontinuation from the study for any other reason.
Dose escalation to 50 mg INC424 bid p.o. is forseen in patients with inadequate response (stable disease or progressive disease ). In patients with AML following 2 weeks of therapy. In patients with CMML a reduction of 50% monocytes is expected. If monocytes reduction is =50% or blast count is stable or increasing, dose is increased to 50 mg bid p.o.
If after further 14 days no response is obtained the therapy will be continued with azacitidine 75 mg/m2 sc qd for 7d and 25 mg bid INC424. After further 14 days and still no response the dose of INC424 is increased to 50 mg bid p.o. in combination with azacitidine 75 mg/m2 sc qd for 7d if the patient has no dose limiting toxicity. If the patient does not respond to the therapy or if unacceptable toxicity due to study medication happens, which do not allow the continuation of the treatment, study treatment will be discontinued and the best standard threrapy will be applied. The study medication will be applied max. for one year, aferwards a one year follow-up will be performed.

Primary Outcome(s)

Phase I
Tolerability and safety of INC424 alone or in combination with azacitidine at day 56 after treatment of 4 patients.
The following clinical and laboratory parameters will be collected to evaluate study drug safety and toxicity (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths):
•duration and severity of all grade adverse events (AEs) by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V4.03)
•performing physical exams (PE)
•evaluating changes in vital signs (VS)
•ECOG performance status
•electro and echocar-diograms
•serum chemistry and hematology results
•Grade 3 and 4 AEs, Serious Adverse Events (SAEs)
•Frequency of dose interruptions and discontinuations due to AEs.
Phase II (after one year treatment of the last patient) - Hematological response defined as:
-CR, CRi, PR, SD in post-myeloproliferative AML (blastic transfor-mation)
-Monocyte count (periphery) and Blast count (bone marrow) reduction in CMML

Secondary Outcome(s)

• Dose limiting toxicity (DLT) during study therapy (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths)
• Leukemia Free Survival one year after start of trial therapy
• Overall survival one year after start of trial therapy
• Progression free survival one year after start of trial therapy
• Transfusion requirement during study therapy (on day 1 of every treatment period (28 days) of study treatment (max. 12 months)
• Effect on Bone Marrow Fibrosis during study therapy (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths)
• Response according to cytogenetics (normal and multiaberrant karyotype) during study therapy (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths)
• Duration of hospitalization for any reason during study therapy (on day 1 of every treatment period (28 days) of study treatment (max. 12 months)
• Incidence of treatment failure according to IWG response criteria during study therapy (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths).
• Correlation of study endpoints (on day 1 of every treatment period (28 days) of study treatment (max. 12 months) with the points achieved at the time of diagnosis according to the following questionnaire: instrumental activities of daily living (iADLs, “Instrumentelle Aktivitäten des täglichen Lebens” and EORTC QLQ-C30 Version 3.0)
• Correlation of study endpoints (on day 1 of every treatment period (28 days) of study treatment (max. 12 months) with the Eastern Cooperative Oncology Group (ECOG) Performance Status at the time of diagnosis
• Comparison of response and survival of patients treated with INC424 as monotherapy and in combination with azacitidine with historical patient populations treated with the conventional chemotherapy
• Response according to JAK2, flt3, npm1 Mutation during study therapy (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths)
• Number of patients undergoing stem cell Transplantation up to end of follow-up (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths)
• Safety of INC424 ± azacitidine (Grade IV toxicities and feasibility of the combination) during study therapy (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths)
The following clinical and laboratory parameters will be collected to evaluate study drug safety and toxicity (on days 15, 28, 42, 56, 84 and all 28 days up to max. 12 moths):
• duration and severity of all grade adverse events (AEs) by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V4.03)
• performing physical exams (PE)
• evaluating changes in vital signs (VS)
• ECOG performance status
• electro and echocar-diograms
• serum chemistry and hematology results
• Grade 3 and 4 AEs, Serious Adverse Events (SAEs)
• Frequency of dose interruptions and discontinuations due to AEs.
• Quality of Life (on day 1 of every treatment period (28 days) of study treatment (max. 12 months):
- Change in ECOG PS from baseline to each visit where measured
- EORTC QLQ-C30 from baseline to each visit where measured
- Change in iADL from baseline to each visit where measured

Secondary ID(s)

2014-000346-30

Source(s) of Monetary Support

Celgene International Sarl

Novartis Pharma GmbH

Ethics review

Status: Approved
Approval date: 04/02/2015
Contact:

[e-mail]

Geschäftsstelle der Ethik-Kommission an der Medizinischen Fakultät der Universität Leipzig c/o Zentrale Poststelle

[phone]

[e-mail]

Results

• Date Completed: 28/02/2018
• URL: http://drks.de/search/en/trial/DRKS00007802#studyResults