Fractionated Gemtuzumab Ozogamicin Followed by Non-engraftment Donor Leukocyte Infusions for Relapsed/Refractory Acute Myeloid Leukemia

• Gemtuzumab Ozogamicin (GO) (Drug), also known as Mylotarg: Patients will be given gemtuzumab ozogamicin on days 1,4, and 7. Capped at 4.5mg individual doses. Total doses capped at 13.5mg.
• Donor Leukocytes (Other): The product will be administered unprocessed on day 8/24 hours post GO (same day as leukapheresis) with a minimum of CD3+ cells and maximum of CD3+ cells/kg irrespective of the number of CD34+ cells.

Primary outcomes

• Phase 1: Determine the RP2D or MTD of Nonengraftment Donor Leukocyte Infusions With Fractionated Gemtuzumab Ozogamicin in Patients With Relapsed/Refractory AML Defined as Dose Level Without Dose Limiting Toxicities. [35 days post infusion]: The MTD of non-engraftment donor leukocyte infusions administered with fractionated gemtuzumab ozogamicin in patients with relapsed/refractory AML is determined by the dose level achieved with no Dose limiting toxicities. Measure = participants without DLTs. The recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD) was evaluated by utilizing a 3+3 design to determine if 1-2x108 CD3 cells/kg can be safely administered with fractionated Gemtuzumab Ozogamicin administered on days 1,4 and 7 (total dose capped at 13.5 mg). The leukocyte infusion is administered on day 8 after completion of GO day 7. Two DLI dose levels well be assessed: DLI Dose Level 1: 1-2x107 CD3+ cells/kg DLI Dose Level 2: 1-2x108 CD3+ cells/kg The RP2D/MTD is determined by the dose level achieved with no Dose limiting toxicities. Measure = participants without DLTs through 35 days post DLI.
• Response Rate [4 weeks post infusion]: Response rate of infusional gemtuzumab ozogamicin followed by nonengraftment donor leukocyte infusions in patients with refractory acute myeloid leukemia. Bone Marrow Biopsy to be done in patients thought to have responded. Complete remission or complete remission with incomplete count recovery, after one cycle of treatment. Rationale for including CRi: CRi has previously been used in gemtuzumab ozogamicin trials because of incomplete platelet recovery seen with this drug.

Secondary outcomes

• Number of Participants Reaching 24 Months Progression Free Survival [Through 2 years post end of treatment]: Progression free survival of infusional gemtuzumab ozogamicin followed by nonengraftment donor leukocyte infusions in patients with refractory acute myeloid leukemia.
• Number of Participants Who Met the Objective for Overall Survival at 2 Years [Through 2 years post end of treatment]: Overall survival of infusional gemtuzumab ozogamicin followed by nonengraftment donor leukocyte infusions in patients with refractory acute myeloid leukemia.
• Number of Participants With Dose Limiting Toxicities as Defined by the Protocol [Start of treatment through 30 days post the final infusion]: Number of participants with dose limiting toxicities following treatment with gemtuzumab ozogamicin followed by nonengraftment donor leukocyte infusions in patients with refractory acute myeloid leukemia. DLT's defined in the protocol as * IBMTR Severity Index C \& D graft versus host disease * Grade 3 or 4 infusion related reaction * Any grade 3 non-hematological toxicities not directly resulting from patient's disease (with some exclusions specified in the protocol) * Any grade 4 related or unrelated non-hematological toxicity not directly resulting from patient's disease * Development of SOS * Discontinuation of treatment due to an adverse event of any grade is considered a DLT unless the AE is clearly and solely related to the underlying disease. All Grade 5 toxicities are considered DLTs unless clearly and solely related to the underlying disease.

Sex: All, ages: 18 Years to any

Inclusion Criteria of Recipient (patient):

* Histologic confirmation of acute myeloid leukemia (AML)
* Recurrence or progression (including refractory disease) of AML after at least 1 prior standard treatment with progression within 6 months from last treatment.
* No curative treatment option is available
* ≥ 4-weeks since prior chemotherapy or radiation to cellular therapy infusion.
* Age equal to or greater than 18 years.
* Patients with a history of invasive second malignancy who are disease free for ≥ 2 years.
* Patients must have an expected life expectancy of at least 2 months at the time of initiation of treatment
* No active systemic infections allowed.
* Patients who have relapsed after standard autologous stem cell infusion are eligible as long as they meet all inclusion criteria and no exclusion criteria. These patients must be out more than 6 months from cell infusion to be eligible for enrollment.
* DLCO ≥ 40% with no symptomatic pulmonary disease.
* LVEF ≥ 40% by MUGA or echocardiogram.
* Creatinine <1.5x ULN or any serum creatinine level associated with a measured or calculated creatinine clearance of >40 mL/min, AST and ALT < 2.5x ULN, Total Bilirubin < 1.5 x ULN
* Women of childbearing potential and sexually active males must use 2 forms of effective contraception method from time of consent through 6 months after completing treatment (whether last treatment is infusion or drug).
* Not pregnant or nursing. Women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to beginning of treatment (drug). Post-menopausal women (surgical menopause or lack of menses ≥12 months) do not need to have a pregnancy test, please document status.
* Performance status ≤ 2 (or KPS 70)

Exclusion Criteria of Recipient (patient):

* Evidence of HIV infection.
* Any uncontrolled severe, concurrent illness which in the opinion of the treating physician would make this protocol treatment unreasonably hazardous for the patient.
* Oxygen dependent obstructive pulmonary disease.
* Failure to demonstrate adequate compliance with medical therapy and follow-up
* Significant medical or psychiatric illness that would impair the ability to participate in protocol therapy.
* Previous allogeneic stem cell transplant
* Patients who have had previous purine analog (fludarabine, pentostatin, 2-CDA) treatment or treatment with alemtuzumab within 1 year of entering the study
* Previous history of Veno-occlusive disease/Sinusoidal Obstruction Syndrome
* Active hepatitis B or C
* Patients with known active central nervous system leukemia
* Patients with prior treatment of Gemtuzumab ozogamicin
* Patients eligible for allogeneic stem cell transplant

Donor Eligibility Criteria * donor eligibility must be documented and assessed by a separate participating physician other than the treating physician of the recipient.

* Donors agree to up to 3 donor leukocyte collections as documented by assessing physician (although it is not required that the same donor is used for all leukocyte infusions it is preferable, therefore agreement is important at screening). This must be documented in writing by treating physician.
* Typing is required at the following loci: HLA A, B, C, and DRB1.
* Patients with a HLA 0/6 to 3/6(using loci A, B, DR) donor match will be able to participate in this protocol.
* Donors must be a first or second degree relative.
* If the patient/recipient is CMV negative, only CMV negative donors are eligible. If the patient/recipient is CMV positive, CMV testing is not required for the donor.
* Although ABO blood type matching is not required given use of apheresis product preference will be made to ABO compatible donors
* Donors must be ≥18 years of age to donate.
* Donor with a history of malignancy other than non-melanoma skin cancers are eligible only if they had a history of a solid tumor malignancy more than five years prior to lymphocyte donation, and are considered to be in longstanding complete remission as documented by a physician. The donor must be healthy and have all testing criteria completed and meet all criteria for stem cell donation.
* The donor will also be assessed by physician who will document behavioral risk for exposure to infectious agents and diseases. Testing will include the following: Human transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease, communicable disease risks associated with xenotransplantation, Chlamydia trachomatis and for Neisseria gonorrhea, Treponema pallidum (syphilis).This will exclude the donor.
* The donor must be in good general health and not have significant cardiopulmonary, renal, endocrine, or hepatic disease as documented in writing by physician.
* B-HCG urine or serum negative if donor is of childbearing potential within 7 days of PBMC procurement. Not applicable for donors who are Post-menopausal (surgical menopause or lack of menses ≥12 months).
* Donors must have adequate venous access so leukapheresis can be performed via standard peripheral IV without the need for placement of a central venous catheter.

Donor Exclusion Criteria:

* Evidence of infection for HIV-1, HIV-2, syphilis, hepatitis B or C, HTLV 1 or 2, WNV, Chagas.
* Uncontrolled diabetes mellitus. If donor has controlled diabetes this must be documented by physician.
* Active or congestive heart failure syndrome from any cause per donor medical history. Approval for participation by Cardiologist required to be sent to BrUOG.
* Full cardiac workup by a Cardiologist is required for any history of congestive heart failure syndrome, conduction abnormalities or history of arrhythmia other than treated atrial fibrillation.
* Active angina pectoris. To be documented by physician
* Oxygen dependent pulmonary disease. To be documented by physician
* History of any lymphoid, myeloid or other non-solid malignancy. To be documented by physician
* Failure to receive full informed consent.
* Inadequate renal and/or hepatic function per medical history. To be documented by physician
* Known history of cirrhosis or active liver disease per medical history. To be documented by physician
* History of transplantation. To be documented by physician.
* A donor in whom plasma dilution sufficient to affect the results of communicable disease testing is suspected, unless: (A) You test a specimen taken from the donor before transfusion or infusion and up to 7 days before recovery of cells or tissue; or (B) You use an appropriate algorithm designed to evaluate volumes administered in the 48 hours before specimen collection, and the algorithm shows that plasma dilution sufficient to affect the results of communicable disease testing has not occurred.
* Clinical situations in which you must suspect plasma dilution sufficient to affect the results of communicable disease testing will exclude the donor. Such situations include, but are not limited to the following:(A) Blood loss is known or suspected in a donor over 12 years of age, and the donor has received a transfusion or infusion of any of the following, alone or in combination:

  1. More than 2,000 milliliters (mL) of blood (e.g., whole blood, red blood cells) or colloids within 48 hours before death or specimen collection, whichever occurred earlier, or
  2. More than 2,000 mL of crystalloids within 1 hour before death or specimen collection, whichever occurred earlier.

Participant flow

Outcome results

• Phase 1: Determine the RP2D or MTD of Nonengraftment Donor Leukocyte Infusions With Fractionated Gemtuzumab Ozogamicin in Patients With Relapsed/Refractory AML Defined as Dose Level Without Dose Limiting Toxicities. (Primary), Count of participants, Participants: Phase 1 Treatment 1: Gemtuzumab Ozogamicin and DLI Dose Level 1 3; Phase 1 Treatment 2: Gemtuzumab Ozogamicin and DLI Dose Level 2 4
• Response Rate (Primary), Count of participants, Participants: Phase 1 Treatment 1: Gemtuzumab Ozogamicin and DLI Dose Level 1 3; Phase 1 Treatment 2: Gemtuzumab Ozogamicin and DLI Dose Level 2 3; Phase 2 Treatment 3 Gemtuzumab Ozogamicin and DLI Dose Level 2 (MTD as Determined by Phase 1) 4
• Number of Participants Reaching 24 Months Progression Free Survival (Secondary), Count of participants, Participants: Phase 1 Treatment 1: Gemtuzumab Ozogamicin and DLI Dose Level 1 0; Phase 1 Treatment 2: Gemtuzumab Ozogamicin and DLI Dose Level 2 0; Phase 2 Treatment 3 Gemtuzumab Ozogamicin and DLI Dose Level 2 (MTD as Determined by Phase 1) 0
• Number of Participants Who Met the Objective for Overall Survival at 2 Years (Secondary), Count of participants, Participants: Phase 1 Treatment 1: Gemtuzumab Ozogamicin and DLI Dose Level 1 0; Phase 1 Treatment 2: Gemtuzumab Ozogamicin and DLI Dose Level 2 0; Phase 2 Treatment 3 Gemtuzumab Ozogamicin and DLI Dose Level 2 (MTD as Determined by Phase 1) 0
• Number of Participants With Dose Limiting Toxicities as Defined by the Protocol (Secondary), Count of participants, Participants: Phase 1 Treatment 1: Gemtuzumab Ozogamicin and DLI Dose Level 1 0; Phase 1 Treatment 2: Gemtuzumab Ozogamicin and DLI Dose Level 2 0; Phase 2 Treatment 3 Gemtuzumab Ozogamicin and DLI Dose Level 2 (MTD as Determined by Phase 1)

Adverse events

Time frame: All-Cause Mortality was assessed up to two years; Toxicity assessment to be done 30 days (+1 week) post last infusion (DLI or GO whichever is last), up to one year; SAEs post 30 days are still to be reported if suspected to be related to leukocyte infusion or GO, up to two years.

Serious adverse events by term

Other adverse events by term

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• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2022-01-10)

• John Reagan, MD, Principal investigator, Brown University Oncology Research Group (BrUOG)