Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04274738
Recruitment Status : Not yet recruiting
First Posted : February 18, 2020
Last Update Posted : April 29, 2020
Sponsor:
Information provided by (Responsible Party):
X4 Pharmaceuticals

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Waldenstrom Macroglobulinemia Drug: Mavorixafor Drug: Ibrutinib Phase 1

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : April 2020
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Mavorixafor and Ibrutinib
Each 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.
Drug: Mavorixafor
Mavorixafor capsules will be administered per dose and schedule specified in the arm.
Other Name: X4P-001

Drug: Ibrutinib
Ibrutinib capsules will be administered per dose and schedule specified in the arm.




Primary Outcome Measures :
  1. Number of Participants With DLTs [ Time Frame: Cycle 1 (28 days) ]
  2. Percent Change From Baseline in Immunoglobulin M (IgM) at Cycle 1 [ Time Frame: Baseline, at the end of Cycle 1 (cycle length = 28 days) ]
  3. Percent Change From Baseline in IgM at Cycle 2 [ Time Frame: Baseline, at the end of Cycle 2 (cycle length = 28 days) ]
  4. Percent Change From Baseline in IgM at Cycle 3 [ Time Frame: Baseline, at the end of Cycle 3 (cycle length = 28 days) ]
  5. Percent Change From Baseline in Hemoglobin (Hgb) at Cycle 1 [ Time Frame: Baseline, at the end of Cycle 1 (cycle length = 28 days) ]
  6. Percent Change From Baseline in Hgb at Cycle 2 [ Time Frame: Baseline, at the end of Cycle 2 (cycle length = 28 days) ]
  7. Percent Change From Baseline in Hgb at Cycle 3 [ Time Frame: Baseline, at the end of Cycle 3 (cycle length = 28 days) ]
  8. Maximum Observed Plasma Concentration (Cmax) of Mavorixafor [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  9. Cmax of Ibrutinib [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  10. Time to Reach Cmax (Tmax) of Mavorixafor [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  11. Tmax of Ibrutinib [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  12. Half-Life (t1/2) of Mavorixafor [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  13. t1/2 of Ibrutinib [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  14. Accumulation Ratio of Mavorixafor [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  15. Accumulation Ratio of Ibrutinib [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  16. Area Under the Concentration-Time Curve (AUC) of Mavorixafor [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  17. AUC of Ibrutinib [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  18. Clearance of Mavorixafor [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  19. Clearance of Ibrutinib [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  20. Volume of Distribution (Vd) of Mavorixafor [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  21. Vd of Ibrutinib [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 6, and 8 to 10 hours post-dose on Day 1 and Day 21 of Cycle 1, 2, and 3 (each cycle length = 28 days) ]
  22. Change From Baseline in AUC of Absolute Neutrophil Count (ANC) at Cycle 1 [ Time Frame: Baseline, at the end of Cycle 1 (cycle length = 28 days) ]
  23. Change From Baseline in AUC of ANC at Cycle 2 [ Time Frame: Baseline, at the end of Cycle 2 (cycle length = 28 days) ]
  24. Change From Baseline in AUC of ANC at Cycle 3 [ Time Frame: Baseline, at the end of Cycle 3 (cycle length = 28 days) ]
  25. Maximal Change From Baseline in ANC Count at Cycle 1 [ Time Frame: Baseline, at the end of Cycle 1 (cycle length = 28 days) ]
  26. Maximal Change From Baseline in ANC Count at Cycle 2 [ Time Frame: Baseline, at the end of Cycle 2 (cycle length = 28 days) ]
  27. Maximal Change From Baseline in ANC Count at Cycle 3 [ Time Frame: Baseline, at the end of Cycle 3 (cycle length = 28 days) ]

Secondary Outcome Measures :
  1. Percent Change From Baseline in Serum IgM Levels at Cycle 6 [ Time Frame: Baseline, at the end of Cycle 6 (cycle length = 28 days) ]
  2. Change From Baseline in Hgb at Cycle 6 [ Time Frame: Baseline, at the end of Cycle 6 (cycle length = 28 days) ]
  3. Major Response Rate [ Time Frame: From Baseline through the end of Cycle 6 (cycle length = 28 days) ]
    Major response rate is defined as percentage of participants with complete response + very good partial response + partial response.

  4. Number of Participants With Adverse Events (AEs) [ Time Frame: From Baseline up to end of study (up to approximately 2 years) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04274738


Contacts
Layout table for location contacts
Contact: Senior Director, Clinical Operations 857-529-5779 patientinfo@x4pharma.com
Contact: Vice President, Clinical Operations patientinfo@x4pharma.com

Locations
Layout table for location information
United States, Colorado
Colorado Blood Cancer Institute
Denver, Colorado, United States, 80215
Contact: Jeffrey Matous, MD         
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02114
Contact: Steven Treon, MD         
Contact    617-632-2681      
Mass General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
Contact: Andrew Branagan, MD         
Contact    617-274-4000      
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Contact: Kim Rankin    713-794-1882    karankin@mdanderson.org   
Sponsors and Collaborators
X4 Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Chief Medical Officer X4 Pharmaceuticals
Layout table for additonal information
Responsible Party: X4 Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04274738    
Other Study ID Numbers: X4P-001-204
2019-003909-95 ( EudraCT Number )
First Posted: February 18, 2020    Key Record Dates
Last Update Posted: April 29, 2020
Last Verified: April 2020

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Waldenstrom Macroglobulinemia
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases