NCT02169791 · REGISTRY CONDITION SEARCH

Nonmyeloablative Haploidentical Transplant Followed by MLN9708

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE2
Status at capture: COMPLETED
Registry last update: 2021-09-02

In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Participants Experiencing Relapse or Progression

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outcome · POSTED

Neutrophil Engraftment

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outcome · POSTED

Time to Platelet Recovery Post Transplant

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outcome · POSTED

Day 30 CD3 Donor Chimerism

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outcome · POSTED

Day 30 CD33 Donor Chimerism

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outcome · POSTED

Graft Versus Host Disease

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Availability of a 3/6 - 5/6 matched (HLA-A, B, DR) related donor * Donor must have negative HLA cross-match in the host vs. graft direction. * Donor must be willing to donate mobilized peripheral blood stem cells * Age ≥ 18 years * Karnofsky status ≥ 70% * One of the following high-risk malignancies: * Chronic Myelogenous Leukemia (chronic phase, resistant and/or intolerant to tyrosine kinase inhibitors (OR) accelerated phase (OR) blast crisis in 2nd chronic phase following induction chemotherapy) * Acute Myelogenous Leukemia (2nd or subsequent complete remission \[CR\] (OR) Primary induction chemotherapy failure, but subsequently entered into a CR(OR) 1st CR with poor risk cytogenetics or molecular markers; or arising from preceding hematological disease) * Myelodysplastic Syndrome (treatment-related, monosomy 7 or complex cytogenetics, IPSS score of 1.5 or greater, Chronic myelomonocytic leukemia \[CMML\]) * Acute lymphocytic leukemia/lymphoblastic lymphoma (2nd or subsequent CR (OR) Primary induction chemotherapy failure, but subsequently entered into a CR (OR) 1st CR with poor risk cytogenetics) * Chronic Lymphocytic Leukemia / Prolymphocytic Leukemia (Duration of remission \<12 months after receiving chemotherapy with a nucleoside analog (OR) High risk features (i.e. 17p deletion), (OR) Second or subsequent relapse) * Hodgkin's or Non-Hodgkin's Lymphoma (including low-grade, mantle cell, and intermediate-grade/diffuse) (Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy or autologous transplantation (AND) Chemoresponsive to most recent salvage therapy * Multiple Myeloma (Presence of a poor risk cytogenetic abnormality \[i.e. 17p, t(4;14)\], Relapse post autologous transplant) Exclusion Criteria: * Poor cardiac function: left ventricular ejection fraction \<40% * Poor pulmonary function: FEV1, FVC, or DLCO \<50% predicted * Poor liver function: bilirubin \>2.5 mg/dl (not due to hemolysis, Gilbert's or primary malignancy), AST/ALT \> 3X ULN * Poor renal function: Creatinine \>2.0 mg/dl or creatinine clearance (calculated creatinine clearance is permitted) \< 40 mL/min * Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive. * Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception * Patients who have any debilitating medical or psychiatric illness which would preclude their giving informed consent or their receiving optimal treatment and follow-up. * Systemic treatment, within 14 days before the first dose of MLN9708, with strong strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort. * Patient has \>/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period. * Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial. * Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment. * Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. * Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. * Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
All patients will receive a haploidentical donor transplant using a conditioning regimen of Fludarabine (Flu), cyclophosphamide (cy) and total body irradiation (TBI) followed by MLN9708.
intervention Names
Drug: MLN9708
label
Haploidentical Transplant
type
EXPERIMENTAL

interventions

arm Group Labels
Haploidentical Transplant
description
MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.
name
MLN9708
type
DRUG

Study design

allocation

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

PREVENTION

Enrollment

count: 29
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
To estimate the incidence of relapse/progression at one-year post-transplant.
measure
Number of Participants Experiencing Relapse or Progression
time Frame
1 year

secondary Outcomes

description
To obtain time to neutrophil engraftment post-transplant
measure
Neutrophil Engraftment
time Frame
1 year
description
To measure the time to platelet recovery post-transplant
measure
Time to Platelet Recovery Post Transplant
time Frame
1 year
description
To measure CD3 donor chimerism post-transplant
measure
Day 30 CD3 Donor Chimerism
time Frame
30 days
description
To measure CD33 donor chimerism at Day 30
measure
Day 30 CD33 Donor Chimerism
time Frame
30 days
description
To measure days to onset of acute graft versus host disease
measure
Graft Versus Host Disease
time Frame
100 days

Full study description

brief Summary: In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.
detailed Description: Overview of Study Design: In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation. Patients will receive a nonmyeloablative haploidentical transplant using a T-cell replete allograft and post-transplant cyclophosphamide as previously described at our center (Bashey et al. J Clin Oncol. 2013; 31(10):1310-6). MLN9708 will be administered once weekly for 3 weeks on a 28 day cycle for one-year post-transplant. Post-transplant immunosuppression will consist of tacrolimus only (MLN9708 will substitute for mycophenolate mofetil as the second GVHD prophylactic medication). The primary endpoint of this trial will be the risk of relapse and/or progression at one-year post-transplant. Experience from the literature suggests that following a nonmyeloablative haploidentical transplant using post-transplant cyclophosphamide (haplo-pCy), the risk of relapse is approximately 50% at one year post-transplant. It is hoped that under this protocol, this rate will be at most 25%. Thus the investigators statistically formalize this study by testing the null hypothesis that p, the PFS rate is 0.25 or less versus the alternative hypothesis that p is greater than 0.5. A sample size of 25 patients gives 90% power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test of a proportion.

Source references

references

citation
Szydlo R, Goldman JM, Klein JP, Gale RP, Ash RC, Bach FH, Bradley BA, Casper JT, Flomenberg N, Gajewski JL, Gluckman E, Henslee-Downey PJ, Hows JM, Jacobsen N, Kolb HJ, Lowenberg B, Masaoka T, Rowlings PA, Sondel PM, van Bekkum DW, van Rood JJ, Vowels MR, Zhang MJ, Horowitz MM. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol. 1997 May;15(5):1767-77. doi: 10.1200/JCO.1997.15.5.1767.
pmid
9164184
type
BACKGROUND
citation
Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, Clift R, Doney K, Martin PJ, Mickelson E, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med. 1989 Jan 26;320(4):197-204. doi: 10.1056/NEJM198901263200401.
pmid
2643045
type
BACKGROUND
citation
Anasetti C, Beatty PG, Storb R, Martin PJ, Mori M, Sanders JE, Thomas ED, Hansen JA. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990 Oct;29(2):79-91. doi: 10.1016/0198-8859(90)90071-v.
pmid
2249952
type
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pmid
12714500
type
BACKGROUND
citation
Kernan NA, Flomenberg N, Dupont B, O'Reilly RJ. Graft rejection in recipients of T-cell-depleted HLA-nonidentical marrow transplants for leukemia. Identification of host-derived antidonor allocytotoxic T lymphocytes. Transplantation. 1987 Jun;43(6):842-7.
pmid
3296349
type
BACKGROUND
citation
Kernan NA, Collins NH, Juliano L, Cartagena T, Dupont B, O'Reilly RJ. Clonable T lymphocytes in T cell-depleted bone marrow transplants correlate with development of graft-v-host disease. Blood. 1986 Sep;68(3):770-3.
pmid
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type
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pmid
9780338
type
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citation
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pmid
15753458
type
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citation
Zuckerman T, Rowe JM. Alternative donor transplantation in acute myeloid leukemia: which source and when? Curr Opin Hematol. 2007 Mar;14(2):152-61. doi: 10.1097/MOH.0b013e328017f64d.
pmid
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type
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pmid
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Lundqvist A, Abrams SI, Schrump DS, Alvarez G, Suffredini D, Berg M, Childs R. Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res. 2006 Jul 15;66(14):7317-25. doi: 10.1158/0008-5472.CAN-06-0680.
pmid
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pmid
18519785
type
BACKGROUND

Source notices and limitations

Discovery and provenance

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Preserved source evidence · Not medical advice