Product manufacturing

This is a Phase 1, open-label, non-randomized, single and multiple dose escalation study designed to evaluate the safety and preliminary efficacy of administering Mana 312 to subjects with AML/MDS after allogeneic HSCT.

This is a Phase 1, open-label, non-randomized, single and multiple dose escalation study designed to evaluate the safety and preliminary efficacy (prevention of, or treatment of relapse) of administering Mana 312 to subjects with AML/MDS after allogeneic HSCT. The study will evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of single and multiple doses of Mana 312. Each cycle of administration of Mana 312 will be 28 days.

In the Escalation Cohorts, subjects with low, intermediate, and adverse/high risk of relapse will be enrolled using a modified 3+3 design. Upon completion of Cycle 1, subjects not experiencing dose-limiting toxicity (DLT) may continue receiving their assigned Mana 312 dose every 28 days for an additional 2 doses unless the subject experiences progressive disease (PD), exhausts their supply of Mana 312, experiences intolerable side effects, is removed by the Investigator, withdraws consent, or the study is terminated. After Cohort 1 has been completed (i.e., a decision has been made to proceed to Cohort 2), enrollment will be limited to subjects with high-risk of relapse AML/MDS (see Inclusion Criterion #4b) until the RP2D is determined).

In the Expansion Cohort, only subjects with high risk of relapse AML/MDS will be enrolled using the RP2D of Mana 312. Subjects in the Expansion Cohort will receive Mana 312 at the time of relapse or at 1 year after HSCT, whichever is first. Subjects not experiencing dose-limiting toxicity (DLT) may continue receiving their assigned Mana 312 dose every 28 days for an additional 2 doses unless the subject experiences progressive disease (PD), exhausts their supply of Mana 312, experiences intolerable side effects, or the study is terminated.

Select Inclusion Criteria:

1. Subject is ≥18 years of age on the day Informed Consent is signed and dated.

2. Subject must have received only one allogeneic HSCT from a related or unrelated donor prior to administration of Mana 312.

3. Subject has a donor who has agreed to donate leukocytes for manufacture of Mana 312 and who is the same donor who provided cells for the subject's current HSCT.

4. a. Prior to HSCT, for Escalation Cohort 1, subject has AML/MDS b. Prior to HSCT, for Escalation Cohorts after Cohort 1 and for the Expansion Cohort, a subject must have high risk of relapse AML/MDS

5. Mana 312 product is available

   The following Inclusion Criteria apply only during the Pre-Infusion Screening Phase, prior to the time of the planned first infusion of Mana 312.

6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 or Karnofsky/Lansky score of ≥ 50.

7. Subjects in the Expansion Cohort must have a relapse of AML/MDS (MRD+ or morphologic relapse)

8. Subject has adequate organ function

Select Exclusion Criteria:

1. Subject has received antibody that affects T-cell number or function
2. Subject has received a donor lymphocyte infusion (DLI) for the current HSCT.
3. Evidence of GVHD ≥ Grade 2 in any organ system, or active bronchiolitis obliterans syndrome, sclerotic GVHD, or symptomatic serositis.
4. Subject has undergone major surgery (excluding minor procedures, eg, placement of vascular access, gastrointestinal/biliary stent, apheresis, or biopsy) < 21 days prior to the first planned infusion of Mana 312.
5. Subject has an active and clinically relevant infection
6. Subject has symptomatic or uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression (radiation therapy to local site for disease control is allowed if ≥ 14 days prior to Screening and all AE from radiation therapy have resolved to ≤ Grade 1 prior to the planned first Mana 312 infusion).
7. Subject has any other medical condition not listed above or social condition that, in the opinion of the Investigator, might place the subject at increased risk, adversely affect compliance, or confound safety or other clinical study data interpretation.