Clinical trial NCT01981850: A Phase 2 Study of RO7490677 In Participants With Myelofibrosis
Official title: A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV MF), Or Post-Essential Thrombocythemia MF (Post-ET MF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Myelofibrosis
Polycythemia Vera
Post-Essential Thrombocythemia Myelofibrosis
Keywords: fibrosis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-11-13
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RO7490677 is an investigational drug that is being developed for possible use in the treatment of myelofibrosis (MF), a disease in which the bone marrow, which is the organ in the body that makes blood cells, is replaced by fibrosis, or excess scar tissue.

The purpose of this study is to gather information on whether RO7490677 has an effect on the MF disease, whether it is safe in patients with MF, and how well it is tolerated.

Detailed description: Stage 1 of this study has completed. Stage 1 was an open-label, Simon two stage, Phase 2 study to determine the efficacy and safety of two different dose schedules of RO7490677 in participants with PMF and post ET/PV MF. There were two treatment cohorts, each assigned to one of two dose schedules receiving either single-agent RO7490677 or RO7490677 in combination with ruxolitinib. Participants were assigned to a weekly or every four week dosing schedule by the investigator.

Stage 2 is a randomized, double-blind Phase 2 study to determine the efficacy and safety of three different doses of RO7490677 in participants with PMF and post ET/PV MF. Participants will be randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of RO7490677. This is the second stage of an adaptive design study as defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, February 2010. Modifications to dose levels, schedule, and regimen have been made in Stage 2 based on data from Stage 1.

Eligibility criteria: Inclusion Criteria:

1. Participants must be ≥18 years of age at the time of signing the Informed Consent Form (ICF);
2. Participants must voluntarily sign an ICF;
3. Participants must have a pathologically confirmed diagnosis of PMF as per the WHO diagnostic criteria or post ET/PV MF;
4. At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow Fibrosis;
5. Intermediate-1, intermediate -2, or high risk disease according to the IWG -MRT Dynamic International Prognostic Scoring System
6. A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 treatment to establish the baseline fibrosis score;
7. Participants must not be candidates for ruxolitinib based on EITHER:

   1. Platelet count \< 50 x 10e9/L, OR
   2. Hgb \< 100 g/L, have received ≥ 2 units PRBC in the 12 weeks prior to study entry, and be intolerant of or had inadequate response to ruxolitinib;
8. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. (Appendix F);
9. Life expectancy of at least twelve months;
10. At least four weeks must have elapsed between the last dose of any MF- directed drug treatments for myelofibrosis (including investigational therapies) and study enrollment;
11. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia;
12. Women of child bearing potential (WCBP), defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤55 years or 12 months if \>55 years, must have a negative serum pregnancy test within four weeks prior to the first dose of study drug and must agree to use adequate methods of birth control throughout the study. Adequate methods of contraception are outlined in the protocol.
13. Ability to adhere to the study visit schedule and all protocol requirements;
14. Must have adequate organ function as demonstrated by the following:

    * ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (if upon judgment of the treating physician, it is believed to be due to extramedullary hematopoiesis \[EMH\] related to MF);
    * Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treating physician, it is believed to be due to EMH related to MF);
    * Serum creatinine ≤ 2.5 mg/dL x ULN.

Exclusion Criteria:

1. White blood cell count \> 25 x 10e9/L or \> 10% peripheral blood blasts;
2. Other invasive malignancies within the last 3 years, except non- melanoma skin cancer and localized cured prostate and cervical cancer;
3. History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months;
4. Presence of active serious infection;
5. Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study;
6. Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, or C infection;
7. Organ transplant recipients other than bone marrow transplant;
8. Women who are pregnant or lactating.

Primary outcomes:
measure: Stage 1 Main Phase: Overall Response Rate (ORR)
timeFrame: Up until and including completion of 6 cycles. Each cycle is 28 days.
measure: Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)
timeFrame: Up until and including completion of 9 cycles. Each cycle is 28 days.
measure: Stage 1 Main + Open-Label Extension (OLE): ORR
timeFrame: From cycle 1 day 1 up until cycle 6, day 29 (Main Phase). From cycle 7 day 1 up until study discontinuation or study termination, up to 83 cycles (OLE). Each cycle is 28 days.
measure: Stage 2 Main + Open-Label Extension (OLE): BMRR
timeFrame: From cycle 1 day 1 up until cycle 9 day 29 (main phase). From cycle 10 day 1 up until study discontinuation or study termination, up to 51 cycles (OLE). Each cycle is 28 days.
Secondary outcomes:
measure: Stage 1 Main Phase: BMRR
timeFrame: Baseline, Weeks 12 and 24
measure: Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes
timeFrame: Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days.
measure: Stage 2 Main Phase: BMRR
timeFrame: Up until and including completion of 9 cycles. Each cycle is 28 days.
measure: Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit
timeFrame: Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days.
measure: Stage 2 Main Phase: Duration of Bone Marrow Improvement
timeFrame: From first decrease from baseline of one grade to time of return to baseline levels, up to cycle 9 of 28-day cycles.
measure: Stage 2 Main Phase: Hemoglobin Improvement
timeFrame: Up until and including completion of 9 cycles. Each cycle is 28 days.
measure: Stage 2 Main Phase: Platelet Improvement
timeFrame: Up until and including completion of 9 cycles. Each cycle is 28 days.
measure: Stage 2 Main Phase: Symptom Improvement
timeFrame: Up until and including completion of 9 cycles. Each cycle is 28 days.
measure: Stage 2 Main Phase: Percentage of Participants With Complete Response (CR), Partial Response (PR), Clinical Improvement (CI), Stable Disease (SD), and Progressive Disease (PD) According to IWG-MRT Criteria
timeFrame: Up until and including completion of 9 cycles. Each cycle is 28 days.
Other outcomes:
measure: Stage 1 Main Phase: Maximum Drug Concentration (Cmax)
timeFrame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
measure: Stage 1 Main Phase: Time to Maximum Concentration (Tmax)
timeFrame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
measure: Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last)
timeFrame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
measure: Stage 1 Main Phase: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)
timeFrame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
measure: Stage 1 Main Phase: Terminal Elimination Half-Life (T1/2)
timeFrame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
measure: Stage 1 Main Phase: Clearance (CL)
timeFrame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
measure: Stage 1 Main Phase: Volume of Distribution (Vd)
timeFrame: Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days
measure: Percentage of Participants With Adverse Events (AEs) and Infusion Related Reactions (IRRs)
timeFrame: Baseline up until 6.75 years
measure: Percentage of Participants With Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation
timeFrame: Baseline up until 6.75 years
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Cancer Center
state: Arizona
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: Atlanta
country: United States
facility: Emory Hospital
state: Georgia
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Vancouver
country: Canada
facility: Providence Health Care
state: British Columbia
city: Toronto
country: Canada
facility: The Princess Margaret Cancer Centre
state: Ontario
city: Paris
country: France
facility: Hospital Saint-Louis
city: Aachen
country: Germany
facility: University Medical Center RWTH Aachen
city: Minden
country: Germany
facility: Johannes Wesling Academic Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Centre
city: Kfar Saba
country: Israel
facility: Meir Medical Centre
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Pesaro
country: Italy
facility: Marche Nord Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid Holland
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: London
country: United Kingdom
facility: Guy's and St. Thomas' Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: