A Phase 1/2, Open Label Study of SL-401 in Combination with Pomalidomide and Dexamethasone In Relapsed and Refractory Multiple Myeloma

This study is a phase 1/2 multicenter, open-label study of SL-401 (tagraxofusp-erzs) in combination with standard doses of pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (MM). The study will be conducted in 2 phases: Phase 1 is the dose-escalation phase to determine the maximum tested dose (MTD) of SL-401 in combination with standard doses of pomalidomide and dexamethasone. In Phase 1, each evaluated SL-401 dose level will incorporate an initial "Run-in Cycle" (i.e. cycle 1) of single agent SL-401 in at least 3 patients; following the Run-in Cycle, patients who have not experienced a dose-limiting toxicity (DLT) will receive combination SL-401/pomalidomide and dexamethasone in cycles 2 and beyond. All patients in Phase 2 will receive 1 cycle of SL-401 monotherapy in cycle 1, followed by combination of SL-401/pomalidomide/dexamethasone in cycle 2 and beyond. The dose of SL-401 will be the MTD of SL-401 or MTD given in combination with pomalidomide/dexamethasone determined during Phase 1.

Inclusion Criteria:

• Eligible patients will be considered for inclusion if they meet all of the following criteria. (All necessary baseline studies for determining eligibility must be obtained within 21 days prior to enrollment.)

  1. Male or female patient who is at least 18 years of age.

  2. Patient has given voluntary written informed consent before performance of any study-related procedures not part of standard (non-investigational) medical care.

  3. Patient has been previously diagnosed with MM based on standard criteria.

  4. Patient has received:

     1. At least 2 prior therapies including a proteasome inhibitor (≥ 2 cycles) and lenalidomide (≥ 2 cycles), and
     2. Has achieved at least stable disease (SD) for ≥ 1 cycle of treatment on ≥ 1 prior treatment, and
     3. Has demonstrated disease progression subsequent to treatment, during or within 90 days following completion of the most recent therapy.

  5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2.

  6. Patient has measurable disease defined as at least 1 of the following:

     1. Serum M protein ≥ 0.5 /dL (≥5 g/L)
     2. Urine M protein ≥ 200 mg/24 hours
     3. Serum free light chain (FLC) assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65)

  7. Clinical Laboratory Inclusion Criteria: The following laboratory results must be met within 14 days (or as stipulated) prior to study drug (treatment) administration:

     1. Absolute neutrophil count (ANC) ≥ 1000 cells/μl (growth factor cannot be used within the previous 7 days).
     2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN).
     3. Platelet count ≥ 50,000/μl (without platelet transfusion in the previous 7 days).
     4. Total bilirubin ≤ 1.5 mg/dL.
     5. Serum creatinine ≤ 2.0 mL/dL and creatinine clearance ≥ 40 mL/min (calculated by the Cockcroft-Gault Equation or per 24 hour urine collection).
     6. Serum albumin ≥ 3.2 g/dL in the absence of receipt of (IV) albumin within the previous 72 hours.
     7. Serum creatine phosphokinase (CPK) ≤ 2.5 × the ULN.
     8. Serum calcium (corrected for albumin) level at or below the ULN range (treatment of hypercalcemia is allowed and patient may enroll if hypercalcemia returns to normal range with standard treatment).

  8. Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal as measured by multigated acquisition scan (MUGA) scan or 2-dimensional echocardiography (ECHO) within 28 days prior to start of therapy and no clinically significant abnormalities on a 12-lead electrocardiogram (ECG).

  9. Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test prior to initiation of the SL-401 Run in Cycle (if required) and repeated with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting Pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control, 1 highly effective method and 1 additional effective method at the same time, at least 28 days before she starts taking Pomalidomide through 30 days after the last dose of Pomalidomide and 60 days after the last dose of SL-401. FCBP must also agree to ongoing pregnancy testing during the entire duration of treatment. Men must agree to use a latex or synthetic condom during sexual contact with a FCBP even if they have had a vasectomy from the time of signing the informed consent form through 60 days after the last dose of Pomalidomide or SL-401. These same patients must not donate sperm. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. All patients enrolled into this study, must agree to be registered in and must comply with all requirements of the Pomalidomide REMS(TM) program.

     • An FCBP is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Exclusion Criteria:

Patients will be ineligible for this study if they meet any 1 of the following criteria:

1. The patient has an active malignancy and/or cancer history that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the Sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease.
2. Prior therapy with SL-401 or received any investigational drug within the prior 30 days or 5 half-lives of the investigational drug, whichever is longer.
3. Prior anti-cancer therapy (chemotherapy, targeted agents, radiotherapy, and immunotherapy) within the prior 14 days except for alkylating agents (e.g., melphalan) within the prior 28 days.
4. Pomalidomide (POM)-refractory disease (i.e., non-responsive to prior POM [either as monotherapy or in combination] or relapse/progressive disease within 60 days of prior POM (either as monotherapy or in combination). Prior POM exposure is permitted, provided the patient's MM is not considered POM-refractory as defined above.
5. Primary refractory MM defined as disease that is non-responsive in patients that have never achieved at least stable disease or better with any therapy.
6. Any > grade 1 (according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], v.4.03) adverse reaction unresolved from previous treatments or not readily managed and controlled with supportive care. The presence of alopecia of any grade and peripheral neuropathy ≤ grade 2 without pain is allowed.
7. Previous allogeneic stem cell transplantation with active graft-versus-host-disease, or treatment with immunosuppressive therapy in the 2 months prior to study entry.
8. Daily requirement for corticosteroids >10 mg prednisone daily (or equivalent); inhaled corticosteroids are permitted.
9. Patient is known to be human immunodeficiency virus positive, or have chronic or active hepatitis B (core- or surface antigen-positive) or active hepatitis C infection.
10. Clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association [NYHA] Class 3 or 4, congestive heart failure, uncontrolled or unstable angina, history of myocardial infarction or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication)
11. Uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
12. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
13. History of erythema multiforme or severe hypersensitivity to prior Immunomodulatory Drugs (IMiDs) such as thalidomide and lenalidomide.
14. The patient is receiving medications that are strong inhibitors of CYP1A2. Patients should have discontinued strong CYP1A2 inhibitors (e.g., ciprofloxacin and fluvoxamine) at least 5 half-lives before beginning study drug.
15. The patient continues to smoke cigarettes, which can induce CYP1A2.
16. Inability to tolerate thromboprophylaxis.
17. Pregnant or breast feeding.

12 months

This study was terminated early due to slow accrual and changes to Sponsor's development program priorities. The third dose level (12 µg/kg/day), for Phase 2, was not investigated.