Intravenous Administration of RGI-2001 in Patient Undergoing Allogenic Hematopoietic Stem Cell Transplantation (AHSCT)

Sponsor

Regimmune Corporation (Industry)

Overall Status

Completed

CT.gov ID

NCT01379209

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

11.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The clinical trial is a Phase 1/2a, open-label, multi-center, dose-escalation study to evaluate the safety, tolerability and pharmacokinetic profile of RGI-2001 in patients undergoing AHSCT, with radiation or non-radiation myeloablative preparative treatment.

The study will be separated into two parts; a dose escalation phase to assess safety, followed by a large expansion phase to further evaluate the pharmacologic effects of either a Maximum Tolerated Dose, Maximum Feasible Dose or optimal pharmacologically active dose of RGI-2001. The initial dose escalation safety portion of the study (Part 1) will include higher risk patients and limit the unrelated donor transplants. After safety is established in part 1 of the study, the second portion of the study will expand the enrollment criteria and allow transplantation by either related or unrelated donors.

This study will endeavor to identify the dose range at which RGI-2001 has an acceptable safety profile, at which biologic activity is observed, and to guide possible dose levels to utilize in later phase studies based on biological activity.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease	Drug: RGI-2001 Drug: Calcineurin Inhibitors Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Conditioning Regimen Procedure: Allogeneic Bone Marrow Transplantation Drug: Methotrexate Drug: Mofetil Mycophenolate Drug: sirolimus	Phase 1/Phase 2

Detailed Description

In Part 1 (Phase 1: Dose Escalation Phase), patients will receive a single intravenous administration of RGI-2001 approximately 30 minutes after completion of the transplant (either allogeneic PBSCs or allogenic bone marrow transplantation (unmodified)) with the dosage based upon the assigned treatment cohort. Eligible patients will be enrolled in five to seven centers in the United States. Patients who are undergoing AHSCT will be enrolled in a sequential group dose-escalating fashion to determine the safety, tolerability, pharmacokinetic profile, and the MTD or MFD of RGI-2001. It is anticipated that up to six dose levels will be evaluated in Part 1, with an option for an additional cohort (Cohort 7) if the MTD is not reached and pharmacodynamic markers suggest higher doses are warranted.

In Part 2 (Expansion Phase), one or more doses below the MTD or MFD will be selected based on a potential correlation between GvHD and biological activity to further assess safety and biologic activity. Approximately 30 patients who are undergoing either allogeneic PBSCs or allogenic bone marrow transplantation (unmodified) will be enrolled in Part 2 of the study.

Patients will be monitored for safety for 29 days after the transplant procedure.

All patients will be followed for 100 days following transplant procedure for the incidence of acute GvHD, according to the Modified Keystone Criteria for grading acute GvHD (Przepiorka D, et al)

Study Design

Study Type:

Interventional

Actual Enrollment :

68 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2a, Open-Label, Multicenter, Dose-Escalation Study to Evaluate the Safety and Tolerability of Intravenous Administration of RGI-2001 in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT)

Study Start Date :

Sep 1, 2011

Actual Primary Completion Date :

Jun 1, 2015

Actual Study Completion Date :

Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RGI-2001 0.001 μg/kg + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols Dose escalation cohort 1 in part 1 of this study will include 2-6 patients	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines
Experimental: RGI-2001 0.01 μg/kg + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols Cohort 2 in part 1 of this study will include 2-6 patients	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines
Experimental: RGI-2001 0.1 μg/kg + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols Cohort 3 in part 1 of this study will include 2-6 patients	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines
Experimental: RGI-2001 1.0 μg/kg + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols Cohort 4 in part 1 of this study will include 2-6 patients	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines
Experimental: RGI-2001 10 μg/kg + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols Cohort 5 in part 1 of this study will include 2-6 patients	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines
Experimental: RGI-2001 100 μg/kg + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols Cohort 6 in part 1 of this study will include 2-6 patients	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines
Experimental: RGI-2001 250μg/kg + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols Cohort 7 in part 1 of this study will include 2-6 patients (optional)	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines
Experimental: RGI-2001 + Standard of Care GVHD Prophylaxis RGI-2001 will be add to standard treatment with a calcineurin inhibitor, in combination with either methotrexate, mycophenolate mofetil, or sirolimus all at doses as per the institutional protocols In part 2 of this study the best dose or doses determined from part 1 will be administered in up to 30 persons.	Drug: RGI-2001 A single administration of RGI-2001 on Day 0 post AHSCT. Other Names: KRN-7000 RGI-7000 Drug: Calcineurin Inhibitors GVHD prophylaxis according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Hematopoietic Stem Cell Transplantation According to institutional guidelines. Drug: Conditioning Regimen Myeloablative preparative treatment according to institutional guidelines. Subjects could have received any number/combinations of treatments. Procedure: Allogeneic Bone Marrow Transplantation According to institutional guidelines Drug: Methotrexate Other Names: Administered for GVHD prophylaxis as per institutional guidelines Drug: Mofetil Mycophenolate Other Names: Administered for GVHD prophylaxis as per institution guidelines Drug: sirolimus Administered for GVHD prophylaxis as per institutional guidelines

Outcome Measures

Primary Outcome Measures

The maximum tolerated dose (MTD) or maximum feasible dose (MFD) of RGI-2001 [By day 29]
The primary outcome measures are: The incidence and severity of adverse events The maximum tolerated dose (MTD) or maximum feasible dose (MFD) of RGI-2001, administered as a single intravenous infusion approximately 30 minutes after AHSCT

Secondary Outcome Measures

Pharmacodynamic Effects [Within 100 days from AHSCT]
Evaluate biomarkers to assess the potential pharmacodynamic effects of RGI-2001 through biomarkers and cytokine assessments. Exploratory biomarkers for efficacy in reducing GvHD include IL-2R, TNFR1, HGF. Cytokines will be evaluated for both safety and for evidence of mechanism of action and include IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, MIG, TNF-α and IFN-γ.
Pharmacokinetics of RGI-2001 [Within first 8 days]
Obtain pharmacokinetic parameters such as Cmax, Cmin, Tmax, AUC and half-life of the study drug in plasma.
Efficacy in reducing the intensity of GvHD [Within the first 100 days after AHSCT]
The time to onset, peak intensity and course of GvHD after the AHSCT procedure will be monitored according to the Modified Keystone Criteria for Acute Graft-Versus-Host Disease.
Optimal Dose of RGI-2001 [Within first 100 days after AHSCT]
Determine optimal doses of RGI-2001 for further evaluation based on pharmacodynamic response and effectiveness in reducing the intensity of GvHD

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject has a hematological malignancy or aplastic anemia (AA) and is undergoing a first allogeneic transplant procedure.
Meet one of the following underlying disease criteria:

Acute myelogenous leukemia (AML) i. First or subsequent morphologic remission b. Acute lymphoblastic leukemia (ALL) i. First or subsequent morphologic remission c. Chronic myelogenous leukemia (CML) i. Chronic phase; or ii. Accelerated phase d. Multiple Myeloma (MM) i. Not more than 20% plasma cells in the bone marrow e. Myelodysplastic syndrome (MDS), including chronic myelomonocytic leukemia (CMML), who have received at least one previous induction regimen and have <10% blasts f. Myeloproliferative disorder (MPD), including; i. myeloid metaplasia, and ii. myelofibrosis g. Non-Hodgkin's Lymphoma (NHL) i. High-risk NHL in first remission; or

Relapsed or refractory NHL h. Hodgkin's lymphoma (HL) beyond first remission i. Aplastic anemia (AA)

Male or female, age ≥18 years of age
Reasonable expectation of survival for at least 3 months, if the transplant procedure is successful
Eastern Cooperative Oncology Group (ECOG) status of 0-2 or Karnofsky Performance Status (KPS) of > 60
Transplant Donor
Part 1 (Phase 1: Dose Escalation Phase):

Unrelated transplant donor with no more than 1 HLA allele or antigen mismatch, defined as loci A, B, C and DR (note: DQ is excluded)

Part 2 (Phase 2a: Expansion Phase):Related or unrelated transplant donor, with no more than 1 HLA allele or antigen mismatch, defined as loci A, B, C and DR (note: DQ is excluded).
Source of the allograft
Part 1 (Phase 1: Dose Escalation Phase):Unmodified (non-manipulated) bone marrow, or mobilized peripheral blood stem cell (PBSC) transplant, using G-CSF as the mobilizing agent.
Part 2: (Phase 2a: Expansion Phase) Unmodified (non-manipulated) bone marrow, or mobilized peripheral blood stem cell (PBSC) transplant, using G-CSF as the mobilizing agent.
Anti-graft-versus-host disease (GvHD) prophylaxis:

A calcineurin inhibitor [either tacrolimus (FK506) or cyclosporin A)], in combination with either methotrexate (MTX), mycophenolate mofetil (MMF) or sirolimus (RAPA) all at doses as per the institutional protocols

Adequate hepatic function, with bilirubin not exceeding the upper limit of normal (except when attributed to Gilbert's Disease), and AST and ALT of less than 1.5 times the upper limit of normal
No clinically significant cardiac conduction disorder on screening ECG
Serum creatinine ≤ 2.0 mg/dL
Female patients of childbearing potential must have a negative serum pregnancy test prior to enrollment and must agree to use dual method of contraception for 30 days after study drug administration. Approved methods of contraception include, an IUD with spermicide, a female condom with spermicide, a diaphragm with spermicide, a cervical cap with spermicide, use of a condom with spermicide by sexual partner or a sterile sexual partner.
If male, subjects must be sterile or willing to use an approved method of contraception from the time of Informed Consent to 30 days after study drug treatment. Males must be willing to refrain from sperm donation within 30 days after study drug treatment.
No clinically significant acute or chronic medical condition that in the opinion of the investigator will interfere with study participation
No clinically significant laboratory abnormalities as determined by the Principal Investigator, in consultation with the Sponsor's Medical Monitor
No active infection
Have signed written informed consent before undergoing any study related procedures and is willing to comply with all study procedures

Exclusion Criteria:

Female subjects who are pregnant or lactating
Subjects about to undergo a non-ablative or non-myeloablative transplant
AML or ALL patient who are in relapse (>5% blasts) or who are defined as primary refractory
Blast crisis CML
Radiation, chemotherapy, immunotherapy in the previous 3 weeks, unrelated to the transplant procedure
Subjects who, in the judgment of the Investigator have not recovered from the effects of previous therapy
Subject who is about to undergo cord blood transplantation
Procedures that are intended to deplete regulatory T-cells from donor transplant materials
Known or suspected HIV infection
Active hepatitis A, B, or C infection in recipient or donor
Uncontrolled active infection requiring IV antibiotics in recipient or donor
Major surgery within 1 month before Day 0
Participation in an investigational study within 1 month prior to Day 0
Prior treatment with anti-CD3 antibodies
Treatment with anti-CD20 antibodies or anti-thymocyte globulin (ATG) within 3 months of the AHSCT procedure (i.e. infusion of transplant material and RGI-2001).
Vaccination within the preceding 2 weeks prior to the planned dose of RGI-2001
Planned vaccination within 2 months after study drug administration
Known history of cardiac dysfunction (e.g. <50% ejection fraction), ischemia, conduction abnormalities, or myocardial infarction in the previous six months
Cardiac pacemaker or automatic implantable cardioverter-defibrillator
Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms
Congenital long QT syndrome or family history of long QT syndrome
History of additional risk factors for torsades de pointes (TdP) (e.g., heart failure, hypokalemia)
Bundle branch block
Connective tissue/rheumatologic disorders
History of autoimmune disease
History of solid tumor, excluding non-melanoma skin or cervical carcinoma after curative resection, within the preceding 5 years
Uncontrolled diabetes
Prior allogeneic hematopoietic stem cell transplantation
Any other prior organ transplant
Psychiatric or addictive disorders that preclude obtaining reliable informed consent
Any other condition that, in the opinion of the investigator, renders the subject unsuitable for study participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD Moores Cancer Research Institute	San Diego	California	United States	93093
2	Stanford School of Medicine	Stanford	California	United States	94305
3	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
4	Ohio State University Comprehensive Cancer Center - The James	Columbus	Ohio	United States	43210
5	Methodist Healthcare System	San Antonio	Texas	United States	78229
6	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109