Clinical Trials /

A Study of Mavorixafor in Combination With Ibrutinib in Participants With Waldenstrom's Macroglobulinemia (WM) Whose Tumors Express Mutations in MYD88 and CXCR4

NCT04274738

Description:

The primary objective of the study is to establish a pharmacologically active dose of mavorixafor in combination with ibrutinib based on pooled safety, clinical response, pharmacokinetic (PK) and pharmacodynamic (PD) data to select the recommended dose for a randomized registrations trial.

Related Conditions:
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Mavorixafor in Combination With Ibrutinib in Participants With Waldenstrom's Macroglobulinemia (WM) Whose Tumors Express Mutations in MYD88 and CXCR4
  • Official Title: A Phase 1b Trial of Mavorixafor, an Oral CXCR4 Antagonist, in Combination With Ibrutinib in Patients With Waldenstrom's Macroglobulinemia (WM) Whose Tumors Express Mutations in MYD88 and CXCR4

Clinical Trial IDs

  • ORG STUDY ID: X4P-001-204
  • SECONDARY ID: 2019-003909-95
  • NCT ID: NCT04274738

Conditions

  • Waldenstrom Macroglobulinemia

Interventions

DrugSynonymsArms
MavorixaforX4P-001Mavorixafor and Ibrutinib
IbrutinibMavorixafor and Ibrutinib

Purpose

The primary objective of the study is to establish a pharmacologically active dose of mavorixafor in combination with ibrutinib based on pooled safety, clinical response, pharmacokinetic (PK) and pharmacodynamic (PD) data to select the recommended dose for a randomized registrations trial.

Detailed Description

      This is an intrapatient dose-escalation study. Three dose levels of mavorixafor will be
      explored: 200 milligrams (mg) once daily (QD) (dose level 1), 400 mg QD (dose level 2), and
      600 mg QD (dose level 3). Ibrutinib will be administered at its labeled dose for participants
      with WM, 420 mg orally QD. Each treatment cycle will be 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Mavorixafor and IbrutinibExperimentalEach participant will receive mavorixafor at 200 mg (2 capsules of 100 mg each) QD in combination with ibrutinib 420 mg (3 capsules of 140 mg each) QD. If the dose is well tolerated with no dose limiting toxicities (DLTs) observed during 28-day DLT observation period (Cycle 1), the participant will receive 400 mg (4 capsules of 100 mg each) QD in combination with ibrutinib during Cycle 2. If participant does not experience a DLT at this dose level at the end of Cycle 2, participant will receive mavorixafor at 600 mg (6 capsules of 100 mg each) QD in combination with ibrutinib during Cycle 3. If participant tolerates 600 mg dose for 28 days and no DLTs are observed, the participant will continue to receive mavorixafor at 600-mg dose in combination with ibrutinib. Once the maximum tolerated dose (MTD) for participant has been identified, the participant may continue to receive treatment for up to 2 years or until disease progression, unacceptable toxicity, death, or study withdrawal.
  • Mavorixafor
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants or their legal representative must be able to sign informed consent

          -  Participants must have a clinicopathological diagnosis of WM and must meet the
             criteria for treatment using consensus panel criteria from the Second International
             Workshop on Waldenstrom's Macroglobulinemia

          -  Participant' WM must have confirmed MYD88L265P and CXCR4WHIM mutations

          -  Participants must have measurable disease, defined as the presence of serum IgM with a
             minimum IgM level of greater than or equal to (≥) 2 * the upper limit of normal (ULN)

          -  Participants may be treatment naïve or have received up to 3 prior treatment regimens
             for WM

          -  Participants must have an ECOG performance status of 0 or 1

          -  Participants must meet the following organ and bone marrow requirements:

             i) Absolute neutrophil count greater than (>) 1,000/microliter (μL) ii) Platelet count
             ≥50,000/μL (platelet transfusion-independent) iii) Hgb ≥8 grams/deciliter (gm/dL) iv)
             Aspartate aminotransferase and alanine aminotransferase less than or equal to (≤) 2.5
             * the ULN and serum total bilirubin ≤1.5 * the ULN, unless secondary to known
             Gilbert's Syndrome or hepatic infiltration by WM, in which case the total bilirubin
             must be ≤3 * the ULN and direct bilirubin ≤1.5 × the ULN v) Serum lipase ≤1.5 * the
             ULN vi) Serum creatinine ≤2 * the ULN or a creatinine clearance of ≥30 milliliters
             (ml)/minute based on the Cockcroft-Gault equation

          -  Women of child-bearing potential (WOCBP) must have a negative pregnancy test

          -  WOCBP who are heterosexually active and male participants with female sexual partners
             of childbearing potential must agree to use an effective method of contraception (for
             example; oral contraceptives, double-barrier methods such as a condom and a diaphragm,
             intrauterine device) during the study and for 4 weeks after the last dose of study
             medication, or to abstain from sexual intercourse for this time; a woman not of
             childbearing potential is one who has undergone a bilateral oophorectomy or who is
             postmenopausal, defined as the absence of menstrual periods for 12 consecutive months

          -  Participants must be willing and capable of complying with the requirements of the
             study

        Exclusion Criteria:

          -  Participants with hyperviscosity syndrome; participants who undergo plasmapheresis for
             hyperviscosity may be considered for enrollment once IgM level is under 4,000 mg/dl

          -  Participants who have known hypersensitivity to mavorixafor or any of its components
             or to ibrutinib

          -  Participants who have previously received a CXCR4 inhibitor or a BTK inhibitor

          -  Participants who are pregnant or breastfeeding

          -  Participants with an infection requiring intravenous antibiotics or hospitalization at
             the scheduled time of the first administration of protocol therapy

          -  Participants with glycated hemoglobin (HbA1c) >6.5%

          -  Participants with central nervous system (CNS) lymphoma; participants with suspected
             CNS lymphoma should undergo appropriate diagnostic studies (magnetic resonance
             imaging, lumbar puncture) before enrollment to determine if CNS lymphoma is present

          -  Participants with ongoing acute clinical AEs of National Cancer Institute Common
             Terminology Criteria for AEs (NCI CTCAE) Grade >1 resulting from prior cancer
             therapies or participants receive prior chemotherapy within 2 weeks of initial dosing
             or prior autologous hematopoietic stem cell transplantation (auto-HSCT) within 6 weeks
             of initial dosing

          -  Participants with a history of, or positive serologies for, human immunodeficiency
             virus (HIV), hepatitis B or hepatitis C infection (participants with HBsAb positivity
             due to a hepatitis B virus [HBV] vaccination are eligible)

          -  Participants who have had within the past 6 months, the occurrence or persistence of
             one or more of the following medical conditions that could not be controlled with
             usual medical care (for example; required emergency care or hospitalization):
             hypertension, diabetes, unstable angina, seizure disorder, or myocardial infarction

          -  Participants with clinically significant cardiac disease, including congestive heart
             failure consistent with New York Heart Association Class 3 or 4; uncontrolled
             hypertension, clinically significant angina, clinically significant arrythmias
             including a history of atrial fibrillation, corrected QT interval using Fridericia
             formula of >470 milliseconds (msec) or a history of prolonged QT syndrome

          -  Participants who have had within the past 6 months the occurrence of one or more of
             the following events: cerebrovascular accident, deep vein thrombosis, pulmonary
             embolism, hemorrhage (NCI CTCAE Grade 3 or Grade 4), or chronic liver disease (meeting
             criteria for Child-Pugh Class B or C)

          -  Participants with prior organ transplantation (prior auto-HSCT are eligible)

          -  Participants who have an uncontrolled bleeding disorder or require an anticoagulant at
             the time of study treatment

          -  Participants with active autoimmune disease requiring systemic steroid administration

          -  Participants with active second malignancies. (except: malignancies that were treated
             curatively and have not recurred within 2 years prior to study treatment; completely
             resected basal cell and squamous cell skin cancers; any non-hematological malignancy
             considered to be indolent and that has never required therapy; and completely resected
             carcinoma in situ of any type)

          -  Participants who have received an investigational agent within 5 half-lives of the
             agent; if the half-life of the agent is unknown, patients must wait 4 weeks

          -  Participants who require strong or moderate inhibitors or inducers of CYP3A4 and
             potent P-gp inhibitors

          -  Participants who require medications which are classified as sensitive CYP2D6
             substrates

          -  Participant who have received in the 2 weeks preceding the first dose of protocol
             treatment, any of the following agents:

             i) Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating
             factor ii) Systemic corticosteroids in a dose of >10 mg equivalent of prednisone
             daily; topical, ophthalmic, intranasal, and inhalational corticosteroids are permitted
             iii) Any other immunomodulating agents, including but not limited to interferon alpha,
             interleukin (IL)-2, mycophenolate, antibodies to tumor necrosis factor (TNF)-α,
             soluble TNF receptors, Janus kinase inhibitors, or IL-23 antagonists

          -  Participants with any other medical, personal, social, or psychiatric condition that,
             in the opinion of the Investigator, may potentially compromise the safety or
             compliance of the participant or precludes the participant's participation in the
             study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With DLTs
Time Frame:Cycle 1 (28 days)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percent Change From Baseline in Serum IgM Levels at Cycle 6
Time Frame:Baseline, at the end of Cycle 6 (cycle length = 28 days)
Safety Issue:
Description:
Measure:Change From Baseline in Hgb at Cycle 6
Time Frame:Baseline, at the end of Cycle 6 (cycle length = 28 days)
Safety Issue:
Description:
Measure:Major Response Rate
Time Frame:From Baseline through the end of Cycle 6 (cycle length = 28 days)
Safety Issue:
Description:Major response rate is defined as percentage of participants with complete response + very good partial response + partial response.
Measure:Number of Participants With Adverse Events (AEs)
Time Frame:From Baseline up to end of study (up to approximately 2 years)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:X4 Pharmaceuticals

Last Updated

February 13, 2020