Phase II Maraviroc for GVHD Prevention

• Sponsor: Abramson Cancer Center of the University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01785810
• Collaborator: (none)
• Enrollment: 37
• Location: 1
• Arm: 1
• Actual Duration (Months): 65.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Successful allogeneic stem-cell transplantation is often limited by graft-versus-host disease (GVHD). Migration of donor cells into tissues plays a major role in GVHD. Drugs that block chemokine receptors such as CCR5, can potentially decrease the migration of donor cells into tissues. Blocking CCR5 after allogeneic stem-cell transplantation may therefore reduce the rates of GVHD.

PURPOSE: This study explores the efficacy of pharmacologic inhibition of CCR5 in prevention of GVHDby administering maraviroc during allogeneic stem-cell transplantation with reduced intensity conditioning.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancy	Drug: Maraviroc 300 mg	Phase 2

Detailed Description

Detailed Description:

PRIMARY OBJECTIVES:

To estimate the cumulative incidence of grade 2-4 acute GVHD by day 180 with the addition of maraviroc to a standard prophylaxis regimen in patients with hematologic malignancies undergoing reduced intensity allogeneic stem-cell transplantation (RIC SCT) from unrelated donors.

SECONDARY OBJECTIVES:

1. To assess the toxicity of a prolonged administration of maraviroc in patients undergoing RIC SCT.

2. To estimate the rates of severe (grade 3-4) acute GVHD by day 100 and 180, grade 2-4 acute GVHD by day 100, organ-specific acute GVHD, chronic GVHD, relapse, infections, non-relapse mortality, use of immunosuppressive therapies and 1-year survival in patients treated with maraviroc after RIC SCT.

3. To assess the effect of treatment with maraviroc on immune recovery, engraftment and donor T-cell chimerism in peripheral blood and in target organs.

4. To assess the effect of donor and recipient CCR5 genotype on the incidence of acute GVHD in patients receiving maraviroc as part of a GVHD prophylaxis regimen.

OUTLINE: Patients receive a standard conditioning regimen with fludarabine and busulfan followed by a peripheral blood stem cell infusion from an unrelated donor, standard GVHD prophylaxis and standard antiviral and antifungal prophylaxis. In addition, all patients receive maraviroc from day -3 to d+ 90.

Patients are followed for 1 year after the stem-cell infusion.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study to Assess the Efficacy of Maraviroc in Prophylaxis of GVHD in Patients With Hematologic Malignancies Undergoing Reduced-Intensity Allogeneic SCT From Unrelated Donors
• Actual Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Nov 11, 2016
• Actual Study Completion Date: Jul 12, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Maraviroc Phase II, single arm, single center trial, assessing the efficacy of the combination of tacrolimus, methotrexate and maraviroc as graft-versus-host disease (GVHD) prophylaxis after unrelated donor peripheral blood stem-cell transplantation in patients with hematologic malignancies. Patients enrolled on this trial will receive a standard conditioning regimen with fludarabine and busulfan followed by a peripheral blood stem cell infusion from an unrelated donor, standard GVHD prophylaxis and standard antiviral and antifungal prophylaxis. In addition, all patients will receive maraviroc from day -3 to d+ 90.

Drug: Maraviroc 300 mg; Patients enrolled on this trial will receive a standard conditioning regimen with fludarabine and busulfan followed by a peripheral blood stem cell infusion from an unrelated donor, standard GVHD prophylaxis and standard antiviral and antifungal prophylaxis. In addition, all patients will receive maraviroc from day -3 to d+ 90.; Other Names: CCR5 Antagonist

Outcome Measures

Primary Outcome Measures

1. Day +180 Rate of Grade II-IV Acute GVHD [180 days]

   The cumulative incidence of grade II-IV acute GVHD by day 180 after the stem-cell infusion. This is based on consensus conference criteria.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients ≥18 years of age with a hematologic malignancy other than aplastic anemia or primary myelofibrosis, scheduled to undergo RIC allogeneic SCT with a peripheral blood stem cell graft from an unrelated donor, using Flu/Bu conditioning and Tac/MTX GVHD prophylaxis. The following diagnoses are included:

• Acute leukemia - AML, ALL or acute biphenotypic leukemia. Patients will have documentation of complete remission within 6 weeks prior to their transplant. Complete remission is defined as <5% blasts on a bone marrow biopsy and absence of any known extramedullary disease.

• Chronic myelogenous leukemia in any stage, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.

• Myelodysplastic syndrome of any subtype, but with documentation of <5% blasts on a bone marrow biopsy within 6 weeks prior to transplant.

• Myeloproliferative disorders other than primary myelofibrosis.

• Lymphoma - All types of lymphoma are eligible.

• CLL and PLL.

• Patients who meet institutional eligibility criteria for allogeneic SCT:

• Renal function: Serum creatinine ≤2.

• Hepatic function: Baseline direct bilirubin, ALT or AST lower than three times the upper limit of normal.

• Pulmonary disease: FVC or FEV1 ≥ 40% predicted.

• Cardiac ejection fraction ≥ 40%.

• Availability of an unrelated donor, identified and screened by the NMDP. The donor will have at least 7/8 HLA-A, -B, -C and -DRB1 matching by high resolution molecular typing and will meet NMDP eligibility criteria to serve as a peripheral blood stem-cell donor.

• Karnofsky score ≥ 70% at the time of screening.

• Capacity to understand and sign the study informed consent form.

• Negative pregnancy test. Women of childbearing potential (not having had a hysterectomy, a bilateral oophorectomy or bilateral tubal ligation, or be post-menopausal with a total cessation of menses of > 1 year) must agree to use documented reliable method(s) of contraception. Men should agree to use condoms during the study period.

• Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed.

Exclusion Criteria

• Patients with aplastic anemia or primary myelofibrosis. Patients with marrow fibrosis secondary to MDS, AML or a myeloproliferative disorder other than primary myelofibrosis are eligible.

• Patients who are not expected to be available for follow-up in our institution for at least 180 days after the transplant.

• Prior allogeneic SCT.

• Uncontrolled bacterial, viral or fungal infections.

• Patients who receive maraviroc for the treatment of HIV infection.

• Patients receiving other investigational drugs for GVHD.

• Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed.

• Patients with prior malignancies are excluded unless treated with curative intent and known to be free of disease for at least 2 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Abramson Cancer Center of the University of Pennsylvania

Investigators

• Principal Investigator: David Porter, MD, Abramson Cancer Center of the University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Abramson Cancer Center of the University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01785810
• Other Study ID Numbers: UPCC 04712
• First Posted: Feb 7, 2013
• Last Update Posted: Jan 11, 2021
• Last Verified: Dec 1, 2020

• Additional relevant MeSH terms: Neoplasms; Hematologic Neoplasms; Maraviroc

Study Results

Participant Flow

Arm/Group Title	Maraviroc
Arm/Group Description	Maraviroc - 300 mg
Period Title: Overall Study
STARTED	37
COMPLETED	29
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Maraviroc
Arm/Group Description	Maraviroc 300 mg
Overall Participants	37
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	14 37.8%
Male	23 62.2%
Comorbidity Index (Count of Participants)
Low	7 18.9%
Intermediate	12 32.4%
High	18 48.6%
Diagnosis (Count of Participants)
Acute myeloid leukemia	27 73%
Myelodysplastic syndrome	6 16.2%
Non-Hodgkin's lymphoma	1 2.7%
Myeloproliferative neoplasms	1 2.7%
Acute lymphoblastic leukemia	2 5.4%
Donor (Count of Participants)
Matched unrelated	31 83.8%
Single-antigen mismatched	6 16.2%
Donor Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	32
Cytomegalovirus Serostatus (Count of Participants)
Recipient positive	18 48.6%
Donor positive	9 24.3%
Negative	10 27%
CD34+ cell dose (x 10^6 cells/kg) [Mean (Full Range) ]
Mean (Full Range) [x 10^6 cells/kg]	6.2
Disease Risk Index (Count of Participants)
Low	3 8.1%
Intermediate	16 43.2%
High/very high	18 48.6%
Donor Sex (Count of Participants)
Male	24 64.9%
Female	13 35.1%
CD3+ cell dose (x 10^8 cells/kg) [Mean (Full Range) ]
Mean (Full Range) [x 10^8 cells/kg]	2.2
CD4+ cell dose (x 10^8 T cells/kg) [Mean (Full Range) ]
Mean (Full Range) [x 10^8 T cells/kg]	1.5
CD8+ cell dose (x 10^8 T cells/kg) [Mean (Full Range) ]
Mean (Full Range) [x 10^8 T cells/kg]	0.7

Outcome Measures

1. Primary Outcome

Title	Day +180 Rate of Grade II-IV Acute GVHD
Description	The cumulative incidence of grade II-IV acute GVHD by day 180 after the stem-cell infusion. This is based on consensus conference criteria.
Time Frame	180 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Maraviroc
Arm/Group Description	Maraviroc - 300 mg
Measure Participants	37
Count of Participants [Participants]	22 59.5%

Adverse Events

Time Frame	From the initiation of maraviroc (Day -3) to d+ 120 days following stem-cell infusion.
Arm/Group Title	Maraviroc
Arm/Group Description	Maraviroc - dose level of 300 mg
All Cause Mortality
	Maraviroc
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Maraviroc
	Affected / at Risk (%)	# Events
Total	5/37 (13.5%)
Blood and lymphatic system disorders
Febrile neutropenia	2/37 (5.4%)	2
Cardiac disorders
Pericardial effusion	1/37 (2.7%)	1
Infections and infestations
Sepsis	2/37 (5.4%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/37 (2.7%)	1
Hypoxia	1/37 (2.7%)	1
Pulmonary edema	1/37 (2.7%)	1
Other (Not Including Serious) Adverse Events
	Maraviroc
	Affected / at Risk (%)	# Events
Total	29/37 (78.4%)
Blood and lymphatic system disorders
Anemia	7/37 (18.9%)
Febrile Neutropenia	1/37 (2.7%)
Cardiac disorders
Pericardial effusion	1/37 (2.7%)
Gastrointestinal disorders
Diarrhea	4/37 (10.8%)
Esophagitis	1/37 (2.7%)
Hemorrhoidal hemorrhage	1/37 (2.7%)
Vomiting	3/37 (8.1%)
Oral pain	1/37 (2.7%)
Rectal mucositis	1/37 (2.7%)
Nausea	4/37 (10.8%)
Oral mucositis	5/37 (13.5%)
Constipation	2/37 (5.4%)
Hemorrhoids	1/37 (2.7%)
Rectal pain	1/37 (2.7%)
Dysphagia	1/37 (2.7%)
Abdominal pain	1/37 (2.7%)
Bloating	1/37 (2.7%)
Abdominal distension	1/37 (2.7%)
Flatulence	1/37 (2.7%)
General disorders
Fatigue	4/37 (10.8%)
Edema limbs	2/37 (5.4%)
Multi-organ failure	1/37 (2.7%)
Fever	1/37 (2.7%)
Investigations
White blood cell decreased	7/37 (18.9%)
Aspartate aminotransferase increased	3/37 (8.1%)
Prolonged partial thromboplastin time	4/37 (10.8%)
Lymphocyte count decreased	7/37 (18.9%)
Alanine aminotransferase increased	3/37 (8.1%)
Hypercalcemia	1/37 (2.7%)
INR Increased	3/37 (8.1%)
Hyperbilirubinemia	3/37 (8.1%)
Alkaline phosphatase increased	1/37 (2.7%)
Decreased platelets	7/37 (18.9%)
Creatinine Elevated	4/37 (10.8%)
Neutropenia	7/37 (18.9%)
Metabolism and nutrition disorders
Hyponatremia	5/37 (13.5%)
Hypoglycemia	1/37 (2.7%)
Hypomagnesemia	3/37 (8.1%)
Hypokalemia	2/37 (5.4%)
Hypocalcemia	4/37 (10.8%)
Anorexia	4/37 (10.8%)
Dehydration	3/37 (8.1%)
Hyperkalemia	3/37 (8.1%)
Hypophosphatemia	2/37 (5.4%)
Hypoalbuminemia	2/37 (5.4%)
Hyperglycemia	6/37 (16.2%)
Tumor lysis syndrome	1/37 (2.7%)
Hypermagnesemia	1/37 (2.7%)
Musculoskeletal and connective tissue disorders
Flank pain	1/37 (2.7%)
Generalized muscle weakness	2/37 (5.4%)
Back pain	1/37 (2.7%)
Neck pain	1/37 (2.7%)
Nervous system disorders
Dysgeusia	1/37 (2.7%)
Peripheral sensory neuropathy	1/37 (2.7%)
Headache	1/37 (2.7%)
Dizziness	1/37 (2.7%)
Depressed level of consciousness	1/37 (2.7%)
Psychiatric disorders
Depression	1/37 (2.7%)
Anxiety	2/37 (5.4%)
Renal and urinary disorders
Hematuria	1/37 (2.7%)
Bladder spasm	1/37 (2.7%)
Urinary retention	1/37 (2.7%)
Respiratory, thoracic and mediastinal disorders
Postnasal drip	1/37 (2.7%)
Dyspnea	2/37 (5.4%)
Sore throat	2/37 (5.4%)
Respiratory failure	1/37 (2.7%)
Epistaxis	1/37 (2.7%)
Hypoxia	1/37 (2.7%)
Skin and subcutaneous tissue disorders
Erythema multiforme	1/37 (2.7%)
Urticaria	1/37 (2.7%)
Pruritus	3/37 (8.1%)
Rash maculopapular	1/37 (2.7%)
Vascular disorders
Hypotension	2/37 (5.4%)
Flushing	1/37 (2.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.