A Phase 2 Study of RO7490677 In Participants With Myelofibrosis

NCT01981850 | Completed Phase 2 Results DMC

• 3 other identifiers: BO42355PRM-151G-1012015-001718-80
• Study Type: interventional
• Target: 125
• Locations: 8 countries
• Sites: 23

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.

Conditions

Primary Myelofibrosis; Polycythemia Vera; Post-Essential Thrombocythemia Myelofibrosis

Keywords

fibrosis

Outcome Measures

Primary Outcomes (4)

• Stage 1 Main Phase: Overall Response Rate (ORR)

  ORR was defined as the percent of participants with a response according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria. This was defined as those participants who achieved clinical improvement (CI), partial remission (PR), or complete remission (CR) at a post-baseline assessment of treatment response OR had at least stable disease (SD) for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease.

  Up until and including completion of 6 cycles. Each cycle is 28 days.

• Stage 2 Main Phase: Bone Marrow Response Rate (BMRR)

  Response rate was defined as the percent of participants with a reduction in bone marrow fibrosis by at least one grade according to World Health Organization (WHO) criteria from baseline to any time during the study. This was determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy.

  Up until and including completion of 9 cycles. Each cycle is 28 days.

• Stage 1 Main + Open-Label Extension (OLE): ORR

  ORR was defined as the percent of participants with a response according to the IWG-MRT criteria. This was defined as those participants who achieved CI, PR, or CR at a post-baseline assessment of treatment response OR had at least SD for three consecutive end-of-cycle response assessments (e.g. Day 1 of the subsequent cycle) in conjunction with improvement in the bone marrow fibrosis score relative to baseline by at least one grade at any time point during the period of stable disease. Participants who achieved a clinical benefit in the main phase had the opportunity to remain on treatment. The determination of ORR in the main phase is outlined in the arms description below. Participants who didn't achieve a benefit had the opportunity to switch to a different dosing schedule in the OLE phase. The determination of ORR in the OLE phase is outlined in the arms descriptions below.

  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.

• Stage 2 Main + Open-Label Extension (OLE): BMRR

  Defined as the percent of participants with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. As determined by a central adjudication panel of expert hematopathologists, blinded to participant, treatment, and time of biopsy. Participants in the main phase had the opportunity to remain on treatment (as outlined in the arms description below). Participants also had the option to switch to the OLE phase after completing 9 cycles of the originally assigned treatment and receive PRM-151 10 mg/kg/Q4W (as outlined in the arms description below).

  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 (9)

• Stage 1 Main Phase: BMRR

  Baseline, Weeks 12 and 24

• Stage 1 Main Phase: Modified Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) Changes

  Baseline, beginning of each cycle (Cycle 2 onward). Each cycle is 28 days.

• Stage 2 Main Phase: BMRR

  Up until and including completion of 9 cycles. Each cycle is 28 days.

• Stage 2 Main Phase: BMRR - Reduction of Bone Marrow Fibrosis by Visit

  Day 1 on Cycles 4, 7, 10 and Cycle 9 Day 29. Each cycle is 28 days.

• Stage 2 Main Phase: Duration of Bone Marrow Improvement

  From first decrease from baseline of one grade to time of return to baseline levels, up to cycle 9 of 28-day cycles.

Other Outcomes (9)

• Stage 1 Main Phase: Maximum Drug Concentration (Cmax)

  Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

• Stage 1 Main Phase: Time to Maximum Concentration (Tmax)

  Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

• Stage 1 Main Phase: Area Under the Curve up to the Last Measurable Concentration (AUC0-last)

  Pre-dose on Cycles(C) 1, 2 and 6, Day(D) 1 and C1 D15. Each cycle is 28 days

Study Arms (7)

Stage 1: Cohort 1 Weekly

EXPERIMENTAL

Participants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 at a dose of 10 mg/kg IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.

Biological: RO7490677

Stage 1: Cohort 1 Every 4 Weeks

EXPERIMENTAL

Paricipants who received no treatment for MF in at least two weeks will be assigned to treatment with single agent RO7490677 at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Biological: RO7490677

Stage 1: Cohort 2 Weekly

EXPERIMENTAL

Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, 5, 8, 15, and 22 of Cycle 1 and Days 1, 8, 15 and 22 of each subsequent 28 day cycle for six cycles.

Biological: RO7490677; Drug: Ruxolitinib

Stage 1: Cohort 2 Every 4 Weeks

EXPERIMENTAL

Participants on a stable dose of ruxolitinib for at least 12 weeks, with no improvement in spleen during the last four weeks will be assigned to receive RO7490677 in combination with ruxolitinib at a dose of 10 mg/kg administered IV on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for six cycles.

Biological: RO7490677; Drug: Ruxolitinib

Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks

EXPERIMENTAL

Participants will be treated with single agent RO7490677 at a dose of 0.3 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.

Biological: RO7490677

Stage 2: Cohort 2 3mg/kg Every 4 Weeks

EXPERIMENTAL

Participants will be treated with single agent RO7490677 at a dose of 3.0 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.

Biological: RO7490677

Stage 2: Cohort 3 10mg /kg Every 4 Weeks

EXPERIMENTAL

Participants will be treated with single agent RO7490677 at a dose of 10 mg/kg IV administered as a 60 minute intravenous infusion on Days 1, 3, and 5 of Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles.

Biological: RO7490677

Interventions

RO7490677 BIOLOGICAL

IV infusion

Also known as: originally called PRM-151, and also known as rhPTX-2

Stage 1: Cohort 1 Every 4 Weeks; Stage 1: Cohort 1 Weekly; Stage 1: Cohort 2 Every 4 Weeks; Stage 1: Cohort 2 Weekly; Stage 2: Cohort 1 0.3mg/kg Every 4 Weeks; Stage 2: Cohort 2 3mg/kg Every 4 Weeks; Stage 2: Cohort 3 10mg /kg Every 4 Weeks

Ruxolitinib DRUG

IV infusion

Also known as: Jakafi

Stage 1: Cohort 2 Every 4 Weeks; Stage 1: Cohort 2 Weekly

Eligibility Criteria

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

You may qualify if:

• Participants must be ≥18 years of age at the time of signing the Informed Consent Form (ICF);
• Participants must voluntarily sign an ICF;
• Participants must have a pathologically confirmed diagnosis of PMF as per the WHO diagnostic criteria or post ET/PV MF;
• At least Grade 2 marrow fibrosis according to the WHO Grading of Bone Marrow Fibrosis;
• Intermediate-1, intermediate -2, or high risk disease according to the IWG -MRT Dynamic International Prognostic Scoring System
• A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1 treatment to establish the baseline fibrosis score;
• Participants must not be candidates for ruxolitinib based on EITHER:
• Platelet count \< 50 x 10e9/L, OR
• 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;
• Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. (Appendix F);
• Life expectancy of at least twelve months;
• 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;
• Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia;
• 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.
• Ability to adhere to the study visit schedule and all protocol requirements;

You may not qualify if:

• White blood cell count \> 25 x 10e9/L or \> 10% peripheral blood blasts;
• Other invasive malignancies within the last 3 years, except non- melanoma skin cancer and localized cured prostate and cervical cancer;
• History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months;
• Presence of active serious infection;
• 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;
• Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B, or C infection;
• Organ transplant recipients other than bone marrow transplant;
• Women who are pregnant or lactating.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (23)

Mayo Clinic Cancer Center

Phoenix, Arizona, 85054, United States

Location

Stanford Cancer Institute

Palo Alto, California, 94304, United States

Location

Emory Hospital

Atlanta, Georgia, 30322, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-2800, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Weill Cornell Medical Center

New York, New York, 10065, United States

Location

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Providence Health Care

Vancouver, British Columbia, V6Z 2A5, Canada

Location

The Princess Margaret Cancer Centre

Toronto, Ontario, M5T 2M9, Canada

Location

Hospital Saint-Louis

Paris, 75475, France

Location

University Medical Center RWTH Aachen

Aachen, D-52074, Germany

Location

Johannes Wesling Academic Medical Center

Minden, 32429, Germany

Location

Hadassah Medical Centre

Jerusalem, 91120, Israel

Location

Meir Medical Centre

Kfar Saba, 4428164, Israel

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, 27100, Italy

Location

Marche Nord Hospital

Pesaro, 61122, Italy

Location

Erasmus Medical Center

Rotterdam, South Holland, 3015 CE, Netherlands

Location

Radboud University Medical Center

Nijmegen, 6525 GA, Netherlands

Location

Guy's and St. Thomas' Hospital

London, United Kingdom

Location

Related Publications (1)

• Verstovsek S, Foltz L, Gupta V, Hasserjian R, Manshouri T, Mascarenhas J, Mesa R, Pozdnyakova O, Ritchie E, Veletic I, Gamel K, Hamidi H, Han L, Higgins B, Trunzer K, Uguen M, Wang D, El-Galaly TC, Todorov B, Gotlib J. Safety and efficacy of zinpentraxin alfa as monotherapy or in combination with ruxolitinib in myelofibrosis: stage I of a phase II trial. Haematologica. 2023 Oct 1;108(10):2730-2742. doi: 10.3324/haematol.2022.282411.

  PMID: 37165840 DERIVED

MeSH Terms

Conditions

Primary Myelofibrosis; Polycythemia Vera; Fibrosis

Interventions

ruxolitinib

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2013
• First Posted: November 13, 2013
• Study Start: October 1, 2013
• Primary Completion: July 10, 2020
• Study Completion: July 10, 2020
• Last Updated: January 5, 2022
• Results First Posted: January 5, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will share

Locations

CA (2); FR (1); US (11); IL (2); DE (2); IT (2); GB (1); NL (2)