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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04274738

Studienbeginn:
April 2020

Letztes Update:
05.03.2021

Wirkstoff:
Mavorixafor, Ibrutinib

Indikation (Clinical Trials):
Waldenstrom Macroglobulinemia

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
X4 Pharmaceuticals

Collaborator:
-

Kontakt

Studienlocations
(3 von 6)

Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Participants 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 symptomatic 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 fibrillationin the last 2 years, 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

Studien-Rationale

Primary outcome:

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:

1. Percent Change From Baseline in Serum IgM Levels Over the Time (Time Frame - Baseline, at each cycle throughout the study (up to approximately 2 years) (cycle length = 28 days))

2. Change From Baseline in Hgb at Over the Time (Time Frame - Baseline, at each cycle throughout the study (up to approximately 2 years) (cycle length = 28 days))

3. Major Response Rate (Time Frame - From Baseline up to end of study (up to approximately 2 years)):
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))

Geprüfte Regime

  • Mavorixafor (X4P-001):
    Mavorixafor capsules will be administered per dose and schedule specified in the arm.
  • Ibrutinib:
    Ibrutinib capsules will be administered per dose and schedule specified in the arm.

Quelle: ClinicalTrials.gov


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