Graft Vs Host Disease
Conditions
Keywords
Allogeneic, Stem Cell, Transplantation
Brief summary
This is a Phase II, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of the Safety and Efficacy of PRO 140 for Prophylaxis of Acute Graft-Versus-Host Disease in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Undergoing Allogeneic Stem-Cell Transplantation.
Detailed description
This is a Phase II, randomized, double-blind, placebo-controlled, multi-center study to evaluate the feasibility of the use of PRO 140 as an add-on therapy to standard GVHD prophylaxis treatment for prevention of acute GVHD in adult patients with AML or MDS undergoing allogeneic HCT. In this study, 60 subjects will be randomized to receive either PRO 140 or placebo in a 1:1 ratio (i.e., 30 subjects per arm). PRO 140 or placebo will be administered as a 350 mg subcutaneous injection on Day -3 or Day -2 prior to stem cell infusion, on the day of stem cell infusion (Day 0), and then weekly for 30 days (at Week 1, Week 2, Week 3 and Week 4) after which it will be administered every two weeks for up to 100±7 days (at Week 6, Week 8, Week 10, Week 12 and Week 14). Subjects will return to clinic for two Follow-up visits at 2 weeks after the last treatment visit, and one year after the first treatment visit.
Interventions
DRUGPRO 140
PRO 140 is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.
DRUGPlacebo
Placebo in parenteral solution.
Sponsors
Amarex Clinical Research
CytoDyn, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Subjects were randomized to the blinded part of the study using an IRT system. Unblinded pharmacists at clinical sites were notified of the arm to which the subjects were enrolled in order to prepare the appropriate treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the following criteria to be included in the study: 1. Patients diagnosed with AML or MDS per below: * Patients with a history of histologically or pathologically confirmed diagnosis of AML and \< 5% blasts in the peripheral blood or bone marrow (per bone marrow aspiration and/or biopsy within 6 weeks prior to screening) scheduled to undergo allogeneic stem-cell transplantation * Patients with a histologically or pathologically confirmed diagnosis of MDS with \< 10% blasts in the bone marrow (per bone marrow aspiration and/or biopsy within 6 weeks prior to screening) scheduled to undergo allogeneic stem-cell transplantation 2. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2 3. Patients must have normal organ function as defined below: Myeloablative allogeneic HCT: * Males and females, age ≥18 and ≤ 65 years of age * Total bilirubin ≤ 2 mg/dL (except in patients with Gilbert's Syndrome) * AST/ALT ≤ 3 times institutional upper limit of normal (except in patients with leukemic infiltration of liver) * Serum creatinine ≤ 2 mg/dL and creatinine clearance ≥ 60 ml/hr * Diffusing capacity of the lung for carbon monoxide (DLCO) \> 50% predicted with no symptomatic pulmonary disease * Cardiac ejection fraction ≥ 50%. If between 40-49% a cardiology consult is required * Clinically normal resting 12-lead ECG at screening visit or, if abnormal, considered not clinically significant by the PI 4. Patients must have a reasonable expectation of ≥ 6 months survival 5. The donor-recipient HLA match criteria required for participation in this protocol are not research subjects in this study and they must meet criteria as National Marrow Donor Program (NMDP) donors. Procedures for selection of donors and stem cell dose will follow FDA requirements for Blood Products (21 CFR 640) and Human Cellular and Tissue Based Products (21 CFR 1271). The standard institutional practices for stem cell transplants also will be followed. The donors are: * HLA-Identical Sibling (6/6): Minimal typing necessary is serologic typing for class I (AB) and molecular typing for class II (DRB1) * Matched Unrelated Donor (8/8): Molecular identity at HLA A, B, C and DRB1 by high-resolution typing * Matched Related and Unrelated Donor (7/8): high-resolution molecular typing at the following loci is required: HLA A, B, C and DRB1 6. Both male and female patients and their partners of childbearing potential must agree to use appropriate birth control methods (birth control pills, barriers, or abstinence) throughout the study duration (excluding women who are not of childbearing potential and men who have been sterilized). Females of childbearing potential must have a negative serum pregnancy test at Screening visit and negative urine pregnancy test prior to receiving the first dose of study drug. 7. Patients must understand and voluntarily sign an informed consent form
Exclusion criteria
Subjects meeting any of the following criteria will be excluded from the study: 1. Patients not expected to be available for follow-up for at least 114 days after transplant 2. Patients who have received prior allogeneic stem cell-transplantation 3. Patients who receive post-transplant high dose cyclophosphamide 4. Patients with active central nervous system (CNS) involvement by malignant cells 5. Patients receiving other investigational drugs for GVHD. Co-enrollment in other clinical trials that do not include experimental GVHD therapies is allowed. 6. Prior use of any experimental or approved CCR5 modulator including maraviroc and PRO 140 7. Patients with uncontrolled bacterial, viral or fungal infections including diagnosis of acute viral hepatitis (defined as any active infection with hepatitis A or a new diagnosis of hepatitis B or C within 24 weeks of dosing) 8. Currently active second malignancy other than non-melanoma skin cancers 9. Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated 10. Patients who are HIV positive 11. Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study 12. Subjects on chronic steroid therapy \> 5 mg/day within 2 weeks of screening except for inhaled, nasal, or topical steroids 13. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Acute GVHD by Day 100 | 100 days from first treatment (100 Days post treatment) | Incidence of Grade II, Grade III or Grade IV acute GVHD by Day-100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Organ-specific Acute GVHD by Day-100 | 100 Days post-treatment | The number and percentages of subjects with organ-specific acute GVHD by Day-100 will be presented by organ category. Chi-square/ Fisher's exact test will be used to compare the incidence between the treatment groups. |
| Donor Engraftment Evaluated by T-cell and Myeloid Chimerism in Peripheral Blood | 365 days post-initial treatment (T1 Visit) (+/- 14 days) | The number and percentages of subjects with donor engraftment failure evaluated by T-cell and myeloid chimerism in peripheral blood will be presented by different treatment groups. Chi-square/ Fisher's exact test will be used to compare the incidence of donor engraftment failure. |
| Neutrophil and Platelet Count Recovery | 100 Days post treatment | The number and percentages of subjects with neutrophil and platelet count recovery will be presented. Chi-square/ Fisher's exact test will be used to compare the incidence of neutrophil recovery and of platelet recovery between treatment groups. |
| Changes in ECOG Performance Score | 100 Days post treatment visit 1 | The raw and change from baseline in ECOG performance score will be summarized for each assessment scheduled visit (i.e., Screening visit, Treatment Visits 1, 4, 7, 9, 11, Follow-up Visit 1and Unscheduled Visit(s)). Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be presented by treatment group. If the Normality assumption is met, t-test will be used to compare the mean of ECOG performance score between the treatment groups and if the Normality assumption is not met, a non-parametric method will be used. |
| GVHD-free Survival (GFS) | 100 Days post treatment visit T1 | GFS will be defined as the elapsed time between the date of transplant until GVHD related death. GVHD-free survival will be compared between the treatment groups using Log-rank test and Kaplan-Meier methods will be used to depict the survival curves. |
| Incidence of Severe and Life-threatening (Grade III and Grade IV) Acute GVHD by Day-100 | 100 Days post-treatment | The number and percentages of subjects with severe and life-threatening (Grade III and Grade IV) acute GVHD by Day-100 will be presented. Chi-square/ Fisher's exact test will be used to compare the incidence between the treatment groups. |
| Frequency of Treatment Emergent Adverse Events and Serious Adverse Events | 100 Days post treatment | Frequency of treatment emergent adverse events and treatment emergent serious adverse events. |
| AML or MDS Relapse Rate by Day-100 | 100 Days post treatment | AML or MDS relapse rate by Day-100 will be summarized and present by treatment groups. |
| Changes and Shifts in Laboratory Measurements Over Time | 365 days post-treatment (+/- 14 days) | Safety Assessment- The laboratory measurements will include Routine CBC, Biochemistry and Urinalysis. * Routine CBC includes hemoglobin, hematocrit (HCT), red blood cell (RBC) count, white blood cell (WBC) count, WBC differential count (%), absolute neutrophils count (ANC) and platelets count. * Biochemistry profile includes assessment of Hepatic function indicators: total and direct bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, Lactate dehydrogenase (LDH); Renal function indicators: Blood Urea Nitrogen (BUN), creatinine; Electrolytes: sodium, potassium, chloride, calcium and bicarbonate; Other: glucose (random), cholesterol (total) * Urinalysis for color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, RBC, WBC, epithelial cells, bacteria, casts, crystals |
| Changes in Electrocardiogram (ECG) Parameters Over Time | 365 days post-treatment (+/- 14 days) | Safety Assessment-The following ECG parameters will be evaluated: ventricular rate (beats per minute), PR interval (msec), QRS interval (msec), QT interval (msec), and QTc interval (msec). |
| Tolerability of Repeated Subcutaneous Administration of PRO 140 as Assessed by Study Participants (Using Visual Analogue Scale) and by Investigator-evaluation of Injection Site Reactions | 365 days post-treatment (+/- 14 days) | All data from tolerability assessments of repeated subcutaneous administration of PRO 140 as assessed by study participants and by investigator-evaluation of injection site reactions will be summarized using n, mean, Standard Deviation (SD), minimum and maximum values. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PRO 140 In this study, 60 subjects will be randomized to receive either PRO 140 or placebo in a 1:1 ratio (i.e. 30 subjects per arm). PRO 140 or placebo will be administered as a 350 mg subcutaneous injection on Day -3 or Day -2 prior to stem cell infusion, on the day of stem cell infusion (Day 0), and then weekly for 30 days (at Week 1, Week 2, Week 3 and Week 4) after which it will be administered every two weeks for up to 100±7 days (at Week 6, Week 8, Week 10, Week 12 and Week 14). Subjects will return to clinic for two Follow-up visits at 2 weeks after the last treatment visit, and one year after the first treatment visit.
PRO 140: Two 1 mL injections, 175mg/ml each, of PRO 140 to opposite sides of the abdomen. | 6 |
| Placebo In this study, 60 subjects will be randomized to receive either PRO 140 or placebo in a 1:1 ratio (i.e. 30 subjects per arm). PRO 140 or placebo will be administered as a 350 mg subcutaneous injection on Day -3 or Day -2 prior to stem cell infusion, on the day of stem cell infusion (Day 0), and then weekly for 30 days (at Week 1, Week 2, Week 3 and Week 4) after which it will be administered every two weeks for up to 100±7 days (at Week 6, Week 8, Week 10, Week 12 and Week 14). Subjects will return to clinic for two Follow-up visits at 2 weeks after the last treatment visit, and one year after the first treatment visit.
Placebo: Two 1 mL injections, 175mg/ml each (placebo contains 5mM Histidine, 15 mM Glycine, 95 mM Sodium Chloride, 0.3% (w/v) Sorbitol, 0.005% (w/v) Polysorbate 20 at a pH of 5.5) to opposite sides of the abdomen. | 5 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Enrolment and treatment halted by sponsor. | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | PRO 140 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 6 Participants | 11 Participants |
| Age, Continuous | 54 years | 43 years | 48 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HIV rapid antigen test HIV rapid antigen test negative | 5 Participants | 6 Participants | 11 Participants |
| HIV rapid antigen test HIV rapid antigen test positive | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment United States | 5 participants | 6 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 0 / 5 |
| other Total, other adverse events | 6 / 6 | 5 / 5 |
| serious Total, serious adverse events | 6 / 6 | 1 / 5 |
Outcome results
Primary
Incidence of Acute GVHD by Day 100
Incidence of Grade II, Grade III or Grade IV acute GVHD by Day-100
Time frame: 100 days from first treatment (100 Days post treatment)
Population: Study was terminated before outcome data could be obtained.
Secondary
AML or MDS Relapse Rate by Day-100
AML or MDS relapse rate by Day-100 will be summarized and present by treatment groups.
Time frame: 100 Days post treatment
Population: Study was terminated before secondary efficacy endpoint data could be obtained.
Secondary
Changes and Shifts in Laboratory Measurements Over Time
Safety Assessment- The laboratory measurements will include Routine CBC, Biochemistry and Urinalysis. * Routine CBC includes hemoglobin, hematocrit (HCT), red blood cell (RBC) count, white blood cell (WBC) count, WBC differential count (%), absolute neutrophils count (ANC) and platelets count. * Biochemistry profile includes assessment of Hepatic function indicators: total and direct bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, Lactate dehydrogenase (LDH); Renal function indicators: Blood Urea Nitrogen (BUN), creatinine; Electrolytes: sodium, potassium, chloride, calcium and bicarbonate; Other: glucose (random), cholesterol (total) * Urinalysis for color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, RBC, WBC, epithelial cells, bacteria, casts, crystals
Time frame: 365 days post-treatment (+/- 14 days)
Population: Trial was terminated before outcome measure data could be obtained.
Secondary
Changes in ECOG Performance Score
The raw and change from baseline in ECOG performance score will be summarized for each assessment scheduled visit (i.e., Screening visit, Treatment Visits 1, 4, 7, 9, 11, Follow-up Visit 1and Unscheduled Visit(s)). Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be presented by treatment group. If the Normality assumption is met, t-test will be used to compare the mean of ECOG performance score between the treatment groups and if the Normality assumption is not met, a non-parametric method will be used.
Time frame: 100 Days post treatment visit 1
Population: Trial was terminated before secondary endpoint data could be obtained.
Secondary
Changes in Electrocardiogram (ECG) Parameters Over Time
Safety Assessment-The following ECG parameters will be evaluated: ventricular rate (beats per minute), PR interval (msec), QRS interval (msec), QT interval (msec), and QTc interval (msec).
Time frame: 365 days post-treatment (+/- 14 days)
Population: Trial was terminated before secondary outcome measure data was obtained.
Secondary
Donor Engraftment Evaluated by T-cell and Myeloid Chimerism in Peripheral Blood
The number and percentages of subjects with donor engraftment failure evaluated by T-cell and myeloid chimerism in peripheral blood will be presented by different treatment groups. Chi-square/ Fisher's exact test will be used to compare the incidence of donor engraftment failure.
Time frame: 365 days post-initial treatment (T1 Visit) (+/- 14 days)
Population: Study was terminated before secondary efficacy endpoint could be obtained.
Secondary
Frequency of Treatment Emergent Adverse Events and Serious Adverse Events
Frequency of treatment emergent adverse events and treatment emergent serious adverse events.
Time frame: 100 Days post treatment
Population: Study was terminated before secondary efficacy endpoint data could be obtained.
Secondary
GVHD-free Survival (GFS)
GFS will be defined as the elapsed time between the date of transplant until GVHD related death. GVHD-free survival will be compared between the treatment groups using Log-rank test and Kaplan-Meier methods will be used to depict the survival curves.
Time frame: 100 Days post treatment visit T1
Population: Study was terminated before secondary efficacy endpoint data could be obtained.
Secondary
Incidence of Organ-specific Acute GVHD by Day-100
The number and percentages of subjects with organ-specific acute GVHD by Day-100 will be presented by organ category. Chi-square/ Fisher's exact test will be used to compare the incidence between the treatment groups.
Time frame: 100 Days post-treatment
Population: Study was terminated before secondary efficacy endpoint data could be obtained.
Secondary
Incidence of Severe and Life-threatening (Grade III and Grade IV) Acute GVHD by Day-100
The number and percentages of subjects with severe and life-threatening (Grade III and Grade IV) acute GVHD by Day-100 will be presented. Chi-square/ Fisher's exact test will be used to compare the incidence between the treatment groups.
Time frame: 100 Days post-treatment
Population: Study was terminated before secondary efficacy endpoint data could be obtained.
Secondary
Neutrophil and Platelet Count Recovery
The number and percentages of subjects with neutrophil and platelet count recovery will be presented. Chi-square/ Fisher's exact test will be used to compare the incidence of neutrophil recovery and of platelet recovery between treatment groups.
Time frame: 100 Days post treatment
Population: Study was terminated before secondary endpoint data could be obtained.
Secondary
Tolerability of Repeated Subcutaneous Administration of PRO 140 as Assessed by Study Participants (Using Visual Analogue Scale) and by Investigator-evaluation of Injection Site Reactions
All data from tolerability assessments of repeated subcutaneous administration of PRO 140 as assessed by study participants and by investigator-evaluation of injection site reactions will be summarized using n, mean, Standard Deviation (SD), minimum and maximum values.
Time frame: 365 days post-treatment (+/- 14 days)
Population: Study was terminated before secondary efficacy endpoint data could be obtained.