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

• Pharmacodynamic Effects [ Time Frame: Within 101 days from AHSCT ] [ Designated as safety issue: Yes ]
  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 [ Time Frame: Within first 8 days ] [ Designated as safety issue: No ]
  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 [ Time Frame: Within the first 101 days after AHSCT ] [ Designated as safety issue: No ]
  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 [ Time Frame: Within first 101 days after AHSCT ] [ Designated as safety issue: No ]
  Determine optimal doses of RGI-2001 for further evaluation based on pharmacodynamic response and effectiveness in reducing the intensity of GvHD

This is a first in man clinical trial that is designed as a two part study in patients undergoing AHSCT. RGI-2001 is believed to have immunomodulating effects that may expand regulatory T-cells and other beneficial cells to modulate the intensity of GvHD after the AHSCT procedure. All patients receive study medication.

In Part 1 (Dose Escalation Phase), patients will receive a single intravenous administration of RGI-2001 approximately 30 minutes after completion of the AHSCT, with the dosage based upon the assigned treatment cohort and body weight. Eligible patients will be enrolled in up to four to six centers in the United States. Patients who are undergoing Allogenic Hematopoietic Stem Cell Transplantation (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 seven dose levels will be evaluated in Part 1, with an option for an additional cohort 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 will be enrolled in Part 2 of the study.

Patients will be monitored for safety for 29 days after AHSCT. All patients in part 1 and 2 of this study will be followed for 100 days following AHSCT for the incidence of acute GvHD.

The clinical trial is a Phase I, 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.

In Part 1 (Dose Escalation Phase), patients will receive a single intravenous administration of RGI-2001 approximately 30 minutes after completion of the AHSCT, with the dosage based upon the assigned treatment cohort. Eligible patients will be enrolled in up to four to six 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 seven dose levels will be evaluated in Part 1, with an option for an additional cohort 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 will be enrolled in Part 2 of the study.

Patients will be monitored for safety for 29 days after AHSCT.

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

Part 1 (Dose Escalation Phase):

Patients undergoing AHSCT will receive a single 30-minute infusion of RGI-2001, commencing approximately 30 minutes after the AHSCT, with the dosage based upon the assigned treatment cohort. The starting dose of 0.001 µg/kg is based on the minimum pharmacologically active (effective) dose in murine GvHD efficacy trials in the mouse, and represents a 400,000-fold lower dose than that tested in GLP mouse toxicology studies with no significant toxicological effects and an exposure over 150,000-fold lower than that at the highest dose tested in the monkey study Dose Escalation.

The initial dose will start at 0.001 ug/kg and increase logarithmically (10x each cohort) to a high dos of 100 ug/kg. An optional dose cohort of 250 ug/kg may be included per the protocol.

In Cohort #1, the first 3 subjects who receive an AHSCT will be treated with RGI-2001 sequentially, with at least a one-week interval between start of therapy for each subject. In any cohort, if dose-limiting toxicity (DLT), as defined in Section 8.5.3, is observed in 1 of 3 subjects, the cohort will be expanded to 6. If at any time, a second subject within the cohort experiences a DLT, enrollment will cease, and safety data for all subjects treated within the cohort will be reviewed by the Principal Investigators and the Medical Monitor to determine if the maximum tolerated dose (MTD), defined as the dose level below which DLT was observed in ≥ 2 (of 3 or of 6) subjects or two or more identical or similar rare events that may be RGI-2001 related were observed within the cohort, e.g., myocardial infarction.

Within any cohort or at any dose at or below the MTD, additional subjects, up to a maximum of 10, may be enrolled.

Doses in between those planned in the above table may also be studied, if deemed appropriate by the Principal Investigators and Medical Monitor.

Patients who are lost to follow-up before Day 29 will be replaced, and patients who have cancelled AHSCT will also be replaced.

All subjects in a given cohort level, minimum of 3, must complete follow-up through Day 29 for adverse events after receiving the post AHSCT IV administration of RGI-2001, the data including laboratory tests (electrolytes, magnesium, BUN, creatinine, LDH, alkaline phosphatase, AST, ALT, total bilirubin, serum cytokine and biomarker levels (IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFN-γ, MIG, TNF-α, IL-2Rα, TNFR1 and HGF), assessment of acute GvHD, and all other toxicity evaluations should be reviewed by the Principal Investigators and the Medical Monitor. These data and recommendations of the Principal Investigators shall be shared with the FDA to gain consensus prior to dose escalation to the next cohort.

The Principal Investigators and the Medical Monitor will evaluate safety data through Day 29 for all patients enrolled in Part 1 and determine if it is acceptable to initiate Part 2 of the study.

Part 2 (Expansion Phase):

The MTD, MFD or a lower pharmacologically active dose from Part 1, will be selected for Part 2 of the study, and a total of approximately 30 patients will be enrolled equally distributed among the dose levels chosen.

Inclusion Criteria:

1. Patients with hematological malignancies or myelodysplastic syndrome undergoing myeloablative therapy and a first allogeneic HSCT (AHSCT)
2. Male or female, age ≥ 18 years of age
3. Eastern Cooperative Oncology Group (ECOG) status of 0-2 or Karnofsky Performance Status (KPS) of > 60

4. Part 1 Dose Escalation AHSCT Procedure:

   1. Patients with hematological malignancies or myelodysplastic syndrome undergoing a first AHSCT procedure and who are in their 2nd or subsequent remission
   2. Type of allograft: Unrelated allogeneic hematopoietic stem cell transplant donor with no more than 1 HLA allele or antigen mismatch.
   3. Source of allograft: Unmodified (non-manipulated) bone marrow.
   4. Anti-graft versus host disease (GvHD) prophylaxis will include a calcineuron inhibitor [either tacrolimus (FK506) or cyclosporin A)], in combination with either methotrexate (MTX) or mycophenolate mofetil (MMF), all at doses as per the institutional protocols.

5. Part 2 Expansion AHSCT Procedure:

   1. Patients with hematological malignancies or myelodysplastic syndrome undergoing a first AHSCT procedure and who are in their 1st (CR1) or subsequent complete remission
   2. Type of allograft: Related or unrelated allogeneic hematopoietic stem cell transplant donors with no more than 1 HLA allele or antigen mismatch.
   3. Source of allograft: Unmodified (non-manipulated), bone marrow or mobilized peripheral blood stem cell transplant (PBSCT) using G-CSF as the mobilizing agent.
   4. Anti-graft versus host disease (GvHD) prophylaxis will include a calcineuron inhibitor [either tacrolimus (FK506) or cyclosporin A)], in combination with either methotrexate (MTX) or mycophenolate mofetil (MMF), all at doses as per the institutional protocols.

Exclusion Criteria:

1. Female patients who are pregnant or lactating
2. Patients about to undergo mini allogeneic transplant (also known as reduced intensity transplant, non-ablative or non-myeloablative transplant, or adoptive immunotherapy)
3. Radiation, chemotherapy, immunotherapy in the previous 3 weeks, unrelated to the AHSCT procedure
4. Patient who is about to undergo cord blood transplantation
5. Procedures that are intended to deplete regulatory T-cells from donor transplant materials
6. Known or suspected HIV infection
7. Active hepatitis A, B, or C infection in recipient or donor
8. Prior treatment with anti-thymocyte globulin, anti-CD20, or anti-CD3 antibodies
9. Cardiac pacemaker or automatic implantable cardioverter-defibrillator
10. Prior autologous or allogeneic hematopoietic stem cell transplantation
11. Any other prior organ transplant