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Title A phase 1 trial of SGN-CD33A in patients with CD33-positive acute myeloid leukemia

IRB SEGE1913

CC 13-1393

Hospital Main Campus

Phase Phase 1

Disease Leukemia - Acute Myeloid (AML)

Description

Primary Objective

• To evaluate the safety and tolerability of SGN-CD33A in patients with CD33-positive acute myeloid leukemia (AML)
• To identify the maximum tolerated dose (MTD) of SGN-CD33A, if one exists at the doses tested
• To evaluate safety and tolerability of treatment with SGN-CD33A when given in combination with azacitidine or decitabine in patients with CD33-positive acute myeloid leukemia (AML)

Secondary Objectives

• To evaluate the safety and tolerability of continued treatment with SGN-CD33A for patients who achieve complete remission (CR) or CR with incomplete blood count recovery (CRi) (Part B of the study)
• To assess the pharmacokinetics (PK) of SGN-CD33A
• To assess the immunogenicity of SGN-CD33A
• To assess the antitumor activity of SGN-CD33A

Additional Objectives

• To assess baseline CD33 expression levels and target (CD33) saturation after treatment
• To assess biomarkers of biological activity, resistance, and predictive biomarkers of response
• To assess the PK/pharmacodynamic relationship of SGN-CD33A
• To assess the effect of SGN-CD33A as a monotherapy on cardiac repolarization (corrected QT interval [QTc] duration)

Inclusion Criteria

1. CD33-positive AML, determined by local pathology and flow cytometry by local laboratory assessment.
2. Patients must have one of the following:
   • Achieved CR with initial induction/consolidation regimen lasting a minimum of 12 weeks (from achievement of CR), have subsequently relapsed, and have received no more than 1 non-myeloablative regimen (e.g., azacitidine, decitabine, low-dose cytarabine) and no additional myeloablative therapy after relapse; relapsed patients in the NPM1 mutated (FLT-3 wildtype) cohort may have received no more than 2 regimens, either myeloablative or non-myeloablative. Hydroxyurea or 6-mercaptopurine are not considered lines of therapy for patients who are otherwise eligible for participation; or
   • Declined high-dose induction/consolidation therapy and have received no more than 2 palliative therapies (e.g., azacitidine, decitabine, low-dose cytarabine) prior to enrollment.
   • Have relapsed APL that has previously been treated with 1 or more prior therapies (e.g. anthracycline and retinoid regimen; arsenic and retinoid regimen)
   • Hypomethylating agent combination cohorts only: Declined high-dose induction/consolidation therapies, have received no more than 2 palliative therapies prior to enrollment, and have not received prior hypomethylating agents.
   • Treatment naive patients (declined high-dose induction/consolidation therapy and have not received a palliative therapy or prior hypomethylating agents), as applicable (See Section 3.1.1.3)
   • Post-allogeneic SCT relapse cohort only:
     • AML post transplant in untreated first relapse
     • History of full donor engraftment prior to relapse (platelets ≥50 x 10⁹/L withouttransfusion and neutrophils ≥500 cells/μl) with ≥95% T-cell donor chimerism
     • With medical monitor approval, patients on stable doses of systemic immunosuppressive therapy for graft-versus-host disease (GVHD) prophylaxis may be eligible for treatment, if not receiving corticosteroids or if the dose of corticosteroids is ≤ prednisone 20 mg/day (or equivalent)
     • No active GVHD, with the exception of Grade 1 skin GVHD
3. Presence of ≥5% blasts in bone marrow is required for:
   • Patients with relapsed disease following intensive chemotherapy (e.g., 7+3 followed by consolidation)
   • Patients diagnosed with AML who have declined high-dose induction/consolidation therapy and have been treated with at least 1 line of palliative therapy APL patients with confirmed molecular relapse (2 consecutive assessments) are not required to have detectable marrow blasts

   Presence of ≥20% blasts in bone marrow is required for patients who have declined high dose induction/consolidation therapy and who have received no prior therapy

4. Age ≥18 years.
5. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (see Appendix F).
6. The following baseline laboratory data:
   • serum direct bilirubin ≤2x upper limit of normal (ULN) or ≤3x ULN for patients with Gilbert's disease
   • serum creatinine ≤2.5x ULN and creatinine clearance ≥30 mL/min
   • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3x ULN
7. Must have central venous access (e.g., peripherally inserted central catheter [PICC], Hickman line, or equivalent) in place prior to first dose of study drug.
8. Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (Β-hCG) pregnancy test result within 7 days prior to the first dose of study treatment and must agree to use an effective contraception method during the study and for 6 months following the last dose of study drug. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy.
9. Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of study drug.
10. Patients must provide written informed consent.
11. Patients who have received consolidative autologous SCT in first CR and are at least 30 days post-transplant are eligible.

Exclusion Criteria

1. Patients with a history of pulmonary fibrosis or diffusing capacity of the lung for carbon monoxide (DLCO) < 50% of predicted.
2. Central nervous system leukemia based on altered neurological status or documented positive cytology in cerebral spinal fluid within the past 6 months.
3. Receipt of non-myeloablative antileukemia chemotherapy or experimental therapy within 14 days of starting study treatment. Hydroxyurea or 6-mercaptopurine used for cytoreduction may be given up to 24 hours prior to treatment.
4. Myeloablative, high-dose chemotherapy (i.e., induction or consolidation therapy) within 4 weeks of starting study treatment.
5. Any uncontrolled Grade 3 or higher (per NCI CTCAE, Version 4.03) viral, bacterial, or fungal infection within 14 days prior to the first dose of study treatment. Antimicrobial prophylaxis or ongoing treatment of resolving/controlled infection is permitted.
6. Patients with previous allogeneic SCT, except for those enrolled in the post-allogeneic SCT relapse cohort.
7. Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to the first dose of study treatment (see Appendix E).
8. Current therapy with other systemic anti-neoplastic or investigational agents.
9. Females who are pregnant or breastfeeding.
10. Known hypersensitivity to monoclonal antibodies or any excipient contained in the drug formulation of SGN-CD33A. For patients in the combination cohorts: hypersensitivity of any excipients of azacitidine or decitabine.