Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haplo PBSCT

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT03018223
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arm: 1
• Actual Duration (Months): 49.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to find out if a combination of drugs (these are called:

cyclophosphamide, sirolimus, and mycophenolate mofetil) will protect participants better against graft vs. host disease (GVHD) after receiving a hematopoietic cell transplant from a related partially matched (haploidentical) donor. As part of the treatment for their blood cancer, participants need a hematopoietic cell transplantation (HCT) to improve their chances of cure. In any HCT, after the stem cell infusion is given, a combination of drugs is needed to prevent GVHD and facilitate acceptance of the graft.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma; Acute Leukemia in Remission; Chronic Myeloid Leukemia; Primary Myelofibrosis; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndromes; Hodgkin Lymphoma; Multiple Myeloma	Drug: Fludarabine; Drug: Busulfan; Drug: Cyclophosphamide; Radiation: Total body irradiation (TBI); Procedure: Peripheral Blood Hematopoietic Cell Transplantation (HCT); Drug: Sirolimus (SIR); Drug: Mycophenolate mofetil (MMF); Drug: Granulocyte-colony stimulating factor (G-CSF)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Calcineurin Inhibitor-Free GVHD Prevention Regimen After Related Haploidentical Peripheral Blood Stem Cell Transplantation
• Actual Study Start Date: Jan 31, 2017
• Actual Primary Completion Date: Dec 15, 2018
• Actual Study Completion Date: Mar 18, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Conditioning/HCT/GVHD Prophylaxis Pre-HCT Conditioning, HCT, GVHD Prophylaxis. Conditioning regimen: To reduce heterogeneity, two commonly used myeloablative (MAC) and reduced intensity (RIC) regimens are permitted on this trial. Myeloablative conditioning: fludarabine, busulfan. Reduced intensity conditioning: fludarabine, cyclophosphamide, total body irradiation. Peripheral blood hematopoietic cell transplantation Graft vs. Host Disease (GVHD) prevention treatment: cyclophosphamide, mycophenolate mofetil, sirolimus. Growth factor support: G-CSF

Drug: Fludarabine; Myeloablative conditioning: 40 mg/m^2 daily for 4 days. Dose will be adjusted for estimated creatinine clearance. Reduced intensity conditioning: 30 mg/m^2 daily on days -6, -5, -4, -3 and -2. Dose will be adjusted for estimated creatinine clearance.; Other Names: Fludara, Oforta ; Drug: Busulfan; Myeloablative conditioning: IV dosing targeted for a daily total area under curve (AUC) 5300 mmol*min/L for 4 days. Busulfan AUC will be pharmacokinetically targeted. An AUC 3500 mmol*min/l may be considered in patients over 60 years of age or with multiple comorbidities. Chemotherapy may start on day -6 or day -5 depending on the day of admission (-6 for Wednesday admission, -5 for Sunday admission).; Other Names: Busulfex, Myleran ; Drug: Cyclophosphamide; Reduced intensity conditioning: 14.5 mg/kg/day on days -6, -5. GVHD prophylaxis: 50 mg/kg ideal body weight (IBW) daily dose will be given on days +3 and +4 post-transplant as an IV infusion over 1-2 hours.; Other Names: Cytoxan ; Radiation: Total body irradiation (TBI); Reduced intensity conditioning: 200 centigray (cGy) on day -1.; Other Names: radiotherapy ; Procedure: Peripheral Blood Hematopoietic Cell Transplantation (HCT); On day 0, patients will receive a peripheral blood hematopoietic cell graft.; Other Names: cell graft ; Drug: Sirolimus (SIR); GVHD prophylaxis: SIR will be administered as a 9 mg oral loading dose on day +5, followed by maintenance. SIR levels will be monitored and maintenance dosing adjusted as needed for a target trough level 8 to 14 ng/ml, per Moffitt BMT program standard practice. In the absence of acute GVHD, sirolimus taper will start on day +90 (+/- 10 days) and it is suggested to finish by day +180.; Other Names: Rapamune ; Drug: Mycophenolate mofetil (MMF); GVHD prophylaxis: MMF will start on day +5 at a dose of 15 mg/kg every 8 hours IV with the maximum daily dose not to exceed 3 gm. MMF will be changed to orally (PO) and discontinued on day +35 (without taper) in the absence of acute GVHD.; Other Names: CellCept ; Drug: Granulocyte-colony stimulating factor (G-CSF); Growth factor support: G-CSF will be given beginning on day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial dose), until absolute granulocyte count (ANC) is > 1,000/mm^3 for three consecutive days. G-CSF may be given IV or subcutaneously.; Other Names: Neupogen, Filgrastim

Outcome Measures

Primary Outcome Measures

1. Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD) [100 days post hematopoietic cell transplant (HCT)]

   Cumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events.

Secondary Outcome Measures

1. Incidence of Chronic GVHD [1 year post HCT]

   Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.

2. Overall Survival (OS) [Up to 1 year post HCT]

   Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.

3. Progression Free Survival (PFS) [Up to 1 year post HCT]

   Progression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Patient Participants:

• Age: Must be older than 18 years, no upper age limit.

• Karnofsky performance status: Full intensity conditioning, 80-100%; reduced intensity conditioning, 60-100%.

• Vital organ function: a) Cardiac: Left ventricular ejection fraction must be > 45% assessed by multigated acquisition (MUGA) scan or echocardiogram. No myocardial infarction within 6 months of transplant evaluation. b) Pulmonary: forced expiratory volume at one second (FEV1), forced vital capacity (FVC), and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) must be ≥ 50% of predicted values. c) Liver: Transaminases (AST, ALT) less than 2 times upper limit of normal values. d) Kidney: Estimated creatinine clearance ≥ 50 cc/min.

• Signed informed consent.

• Included disease conditions and remission status: a) Acute leukemia in First Complete Remission (CR1) or second/subsequent CR. b) Chronic myeloid leukemia, primary myelofibrosis, chronic myelomonocytic leukemia. c) Int-2 or high risk myelodysplastic syndrome (MDS). d) Hodgkin lymphoma beyond CR1 with chemosensitive disease, Stable Disease (SD) may be included if no mass >3 cm. e) Non-Hodgkin lymphoma in high risk CR1 or subsequent CR (by clinical, cytogenetic or molecular criteria), primary induction failure (PIF) or relapsed with chemosensitive disease. SD may be included if no mass >3 cm. f) Multiple myeloma in CR/Very Good Partial Response (VGPR).

Donor Participants:

• Per Moffitt Cancer Center (MCC) Blood and Marrow Transplant (BMT) program practices, an allele level matched (8/8 HLA A, B, C and DR) sibling or unrelated donor is preferred. If a matched donor is not found, mismatched unrelated or haploidentical donors may be considered.

• If a haploidentical donor is considered, parents, children, full siblings and in selected cases, extended family, will have high resolution typing at the MCC HLA laboratory. A familiar haploidentical donor is chosen among those who share at least one HLA-A, B, C, DRB1 and DQB1 haplotype with the patient.

• Patient will be screened for antibodies targeting mismatched HLA antigens in potential haploidentical donors (donor specific antibodies, DSA). Antibody screen and confirmatory testing using Luminex single antigen-bead test will be done.

• Among several potential donors, will choose in order of priority: a) Matched cytomegalovirus (CMV) immunoglobulin G (IgG) serologic status between donor and recipient. b) ABO blood group system-matched donor preferred, then minor ABO mismatch, then major ABO mismatch. c) Younger donor preferred: child, then sibling, and then parent. d) For male recipient, male donor will be preferred. Avoid mother as a donor unless no other choices.

Exclusion Criteria:

Patient Participants:

• Uncontrolled active bacterial, viral, fungal infection.

• Prior allogeneic HCT.

• Unwilling to comply with study requirements.

• Active, progressive or advanced disease based on diagnosis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute

Investigators

• Principal Investigator: Nelli Bejanyan, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 13, 2018

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT03018223
• Other Study ID Numbers: MCC-18766
• First Posted: Jan 11, 2017
• Last Update Posted: Sep 16, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Acute leukemia in CR; Chronic myeloid leukemia; Non-Hodgkin lymphoma in high risk; Graft vs. Host Disease; GVHD; Hematopoietic cell transplant (HCT)
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Myeloid; Multiple Myeloma; Lymphoma, Non-Hodgkin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Primary Myelofibrosis; Mycophenolic Acid; Sirolimus; Cyclophosphamide; Busulfan; Fludarabine; Lenograstim

Study Results

Participant Flow

Arm/Group Title	Conditioning/HCT/GVHD Prophylaxis
Arm/Group Description	Pre-HCT Conditioning, HCT, GVHD Prophylaxis.
Period Title: Overall Study
STARTED	32
COMPLETED	32
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Conditioning/HCT/GVHD Prophylaxis
Arm/Group Description	Pre-HCT Conditioning, HCT, GVHD Prophylaxis.
Overall Participants	32
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	27 84.4%
>=65 years	5 15.6%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	49.5
Sex: Female, Male (Count of Participants)
Female	12 37.5%
Male	20 62.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 12.5%
Not Hispanic or Latino	28 87.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 9.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 21.9%
White	22 68.8%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	32 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Grade II-IV Acute Graft vs. Host Disease (GVHD)
Description	Cumulative incidence of grade II-IV acute GVHD by day 100 after HCT. Acute GVHD organ staging and assessment of overall grade will use standard consensus criteria. The cumulative incidence of acute and chronic GVHD will be estimated, considering malignancy relapse and non-relapse death as competing risk events.
Time Frame	100 days post hematopoietic cell transplant (HCT)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Conditioning/HCT/GVHD Prophylaxis
Arm/Group Description	Pre-HCT Conditioning, HCT, GVHD Prophylaxis.
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants]	18.8 58.8%

2. Secondary Outcome

Title	Incidence of Chronic GVHD
Description	Cumulative incidence of chronic GVHD by 1 year. Chronic GVHD diagnosis follow National Institutes of Health (NIH) Consensus guidelines.
Time Frame	1 year post HCT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Conditioning/HCT/GVHD Prophylaxis
Arm/Group Description	Pre-HCT Conditioning, HCT, GVHD Prophylaxis.
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants]	20.0 62.5%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as time from transplant to death or last follow-up, and is reported as percentage of surviving participants.
Time Frame	Up to 1 year post HCT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Conditioning/HCT/GVHD Prophylaxis
Arm/Group Description	Pre-HCT Conditioning, HCT, GVHD Prophylaxis.
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants]	70.2 219.4%

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression-free survival defined by the time interval from transplant to relapse/recurrence, to death or to last follow-up. Reported as percentage of participants who are disease free one year post HCT.
Time Frame	Up to 1 year post HCT

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Conditioning/HCT/GVHD Prophylaxis
Arm/Group Description	Pre-HCT Conditioning, HCT, GVHD Prophylaxis.
Measure Participants	32
Number (95% Confidence Interval) [percentage of participants]	56.6 176.9%

Adverse Events

Time Frame	2 years, 7 months
Arm/Group Title	Conditioning/HCT/GVHD Prophylaxis
Arm/Group Description	Pre-HCT Conditioning, HCT, GVHD Prophylaxis.
All Cause Mortality
	Conditioning/HCT/GVHD Prophylaxis
	Affected / at Risk (%)	# Events
Total	5/32 (15.6%)
Serious Adverse Events
	Conditioning/HCT/GVHD Prophylaxis
	Affected / at Risk (%)	# Events
Total	17/32 (53.1%)
Blood and lymphatic system disorders
Anemia	1/32 (3.1%)	1
Blood and lymphatic system disorders -Other	1/32 (3.1%)	1
Cardiac disorders
Cardiac disorders - Other	1/32 (3.1%)	1
Gastrointestinal disorders
Colonic perforation	2/32 (6.3%)	2
Nausea	1/32 (3.1%)	1
Upper gastrointestinal hemorrhage	1/32 (3.1%)	1
Vomiting	1/32 (3.1%)	1
Fever	1/32 (3.1%)	1
Hepatobiliary disorders
Hepatobiliary disorders - Other	1/32 (3.1%)	1
Immune system disorders
Autoimmune disorder	1/32 (3.1%)	1
Immune system disorders - Other	1/32 (3.1%)	1
Infections and infestations
Enterocolitis infectious	1/32 (3.1%)	1
Infections and infestations -Other	3/32 (9.4%)	3
Lung infection	3/32 (9.4%)	3
Sepsis	2/32 (6.3%)	2
Urinary tract infection	1/32 (3.1%)	1
Psychiatric disorders
Confusion	1/32 (3.1%)	1
Renal and urinary disorders
Portal vein thrombosis	1/32 (3.1%)	1
Cystitis noninfective	1/32 (3.1%)	1
Hematuria	5/32 (15.6%)	5
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/32 (3.1%)	1
Pleural effusion	1/32 (3.1%)	1
Pneumonitis	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders - Other	1/32 (3.1%)	1
Vascular disorders
Thromboembolic event	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Conditioning/HCT/GVHD Prophylaxis
	Affected / at Risk (%)	# Events
Total	5/32 (15.6%)
General disorders
Fever	4/32 (12.5%)	4
Infections and infestations
Infections and Infestations - Other	1/32 (3.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.