A Study to Find the Maximum Tolerated Dose of the Experimental Combination of the Drugs INC424 and BKM120 in Patients With Primary or Secondary Myelofibrosis

NCT01730248 | Terminated Phase 1

• 1 other identifier: CINC424A2104
• Study Type: interventional
• Target: 63
• Locations: 8 countries
• Sites: 14

Brief Summary

The purpose of this phase Ib clinical trial is to evaluate the safety of the combination of INC424 and BKM120 in the myelofibrosis population and to establish the maximum tolerated dose and or the Recommended Phase II dose of the combination guided by the Bayesian dose escalation model. INC424 has shown efficacy in myelofibrosis (MF) and is approved in the US and EU for the treatment of MF. BKM120 is a PI3K inhibitor. Preclinical and early clinical experience support inhibition of the PI3K/mTOR pathway in MF as aberrant activation of the pathway has been observed in MF models and may contribute to the pathogenesis of the disease.

Conditions

Myelofibrosis

Keywords

Myelofibrosis,; PMF,; PPV-MF,; PET-MF,; Primary Myelofibrosis,; Post-polycythemia vera myelofibrosis,; Post-essential thrombocythemia myelofibrosis

Outcome Measures

Primary Outcomes (1)

• Incidence of dose limiting toxicities

  The incidence of dose limiting toxicities will be analyzed to establish the maximum tolerated dose. To assess the maximum tolerated dose, labs and adverse events are monitored.

  baseline, when the maximum tolerated dose is established.

Secondary Outcomes (14)

• Frequency of adverse events

  after each cohort is enrolled at baseline until the maximum tolerated dose is established

• Frequency of serious adverse events

  after each cohort is enrolled at baseline until the maximum tolerated dose is established

• Abnormalities in vital signs

  baseline, days 2, 8, 15, 22 of cycle 1, day 1 and 15 at Cycle 2, Day 1 from cycle 3 to 12, day 28 on Cycle 12 and every 12 weeks from Week 60 to 96 and at End of treatment

• Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA

  Day 1, 2, 5, 8, 11, 18, 22, 25 of cycle 1, weekly in cycle 2, then at every scheduled visit including End of treatment visit

• Maximum plasma concentration (Cmax)

  pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8

Study Arms (2)

JAK Inhibitor Naive

EXPERIMENTAL

Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period ( 6 or more cycles of 28 days, with visits every 28days for 6 cycles and then visits every 12 weeks) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine maximum tolerated dose (MTD) / Recommended Phase II dose (RPIID) \& an Expansion Phase

Drug: INC424; Drug: BKM120

Prior JAK Inhibitor

EXPERIMENTAL

Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 or more cycles of 28 days, with visits every 28 days for 6 cycles then visits every 12 weeks) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine MTD / RPIID \& an Expansion Phase

Drug: INC424; Drug: BKM120

Interventions

INC424 DRUG

5 mg tablets administered orally twice daily

JAK Inhibitor Naive; Prior JAK Inhibitor

BKM120 DRUG

10 mg and 50 mg hard gelatin capsules administered orally once daily

JAK Inhibitor Naive; Prior JAK Inhibitor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosed with PMF, PPV-MF or PET-MF irrespective of JAK2 mutation status
• Myelofibrosis patients requiring therapy must be classified as intermediate risk level 1 )1 or more prognostic factors defined by IWG) with at least one criteria other than age
• Must have palpable spleen of at least 5 cm from the costal margin to the point of greatest splenic profusion at Screening
• Must have active symptoms of MF (one symptom score of at least 5 or two symptom scores of at least 3 at Screening) (per MFSSF 0-10)
• PLT counts \> or = 75X 10\^9/L at Screening or Cycle 1 Day 1 (not with aid of transfusions

You may not qualify if:

• Pregnant or nursing women
• WOCBP not using highly effective methods of contraception
• Sexually active males who refuse condom use
• Previous Treatment with one of the following: PI3 K inhibitors and AKT inhibitors; JAK inhibitors that resulted in clinically significant toxicities per the Investigator;
• Patients who have had splenic irradiation within 12 months prior to Screening
• Patients with specific mood disorders
• Any history of bleeding diathesis
• Patients receiving the following treatments / medications:
• EIAED within 2 wks. prior to study treatment; medication known to prolong QT interval or induce Torsades de Pointes; treatment with potent systemic systemic inhibitor or systemic inducer of CYP3A4; any use of drug that interferes with coagulation or inhibits PLT function
• current and willing candidates for a stem cell transplantation

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Incyte Corporation: collaborator

Study Sites (15)

Novartis Investigative Site

Herston, Queensland, 4029, Australia

Location

Novartis Investigative Site

Melbourne, Victoria, 3000, Australia

Location

Novartis Investigative Site

Vienna, A-1090, Austria

Location

Novartis Investigative Site

Paris, 75010, France

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Rostock, 18057, Germany

Location

Novartis Investigative Site

Jerusalem, 91120, Israel

Location

Novartis Investigative Site

Ramat Gan, 5265601, Israel

Location

Novartis Investigative Site

Florence, FI, 50134, Italy

Location

Novartis Investigative Site

Varese, VA, 21100, Italy

Location

Novartis Investigative Site

Singapore, 169608, Singapore

Location

Novartis Investigative Site

Madrid, 28041, Spain

Location

Novartis Investigative Site

Edgbaston, Birmingham, B15 2WB, United Kingdom

Location

Novartis Investigative Site

London, NW1 2BU, United Kingdom

Location

Novartis Investigative Site

London, SE1 9RT, United Kingdom

Location

Related Links

• Results for INC424A2104 can be found on the Novartis Clinical Trial Results Website

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

ruxolitinib; NVP-BKM120

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2012
• First Posted: November 21, 2012
• Study Start: December 18, 2012
• Primary Completion: September 28, 2017
• Study Completion: September 28, 2017
• Last Updated: December 19, 2020

Record last verified: 2019-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); IL (2); SG (1); GB (3); DE (2); FR (1); ES (1); IT (2)