Phase I/II, Multicenter, Open Label, Clinical Trial to evaluate safety and efficacy and determine the Maximum Tolerated Dose (MTD) of Filanesib in combination with pomalidomide and dexamethasone in relapsed/refractory (R/R) Multiple Myeloma (MM) patients

National, multicenter, open label single-arm, non-comparative study, that will evaluate the MTD and the efficacy of the Kinesin Spindle Protein (KSP) inhibitor Filanesib (ARRY-520) in combination with pomalidomide + dexamethasone in relapsed or refractory MM patients.

For this purpose, relapsed or refractory MM patients after at least two prior lines of therapy including bortezomib and lenalidomide, who are refractory or intolerant to lenalidomide and refractory to the last line of therapy will be treated with 28-day cycles of Filanesib administered iv as a 1-hour (± 10-minute) infusion at escalating doses on days 1, 2, 15 & 16, + pomalidomide administered po at escalating doses during 21 days with 7 days rest period + dexamethasone at a fixed dose of 40 mg po days 1, 8, 15 & 22. G-CSF prophylaxis is mandatory in all patients after Filanesib, starting from Day 3 and Day 17 (for a total of 7 days each). Treatment will be continued until progression or unacceptable toxicity.

Initially, a Phase I will be conducted using a modified 3+3 dose-escalating algorithm. The first three patients will be enrolled in the first dose level (see Figure 1 for dose escalation levels). If no DLT occurs among them, the next cohort of three patients will continue at the next higher dose level. If a DLT occurs among the first three evaluable patients during the first cycle, three more patients will be enrolled at the same dose level.

If no more than one DLT is observed among the six evaluable patients in this expanded dose group during cycle 1, enrollment will continue at the next higher dose level following the same scheme.

If more than one DLT occurs among the three or six evaluable patients included in the 1st cohort, an alternative dose escalation will be started, with a reduction of the dose of pomalidomide (see Figure 1). Patients will be then treated following again the same 3+3 algorithm. If more than one DLT out of three or six patients occur at the first dose level of the alternative escalation, the study will be stopped.

MTD will be considered as the dose level in which ≤1 DLT are observed among 6 evaluable patients, therefore, at least six patients must be treated at a given dose before this dose is considered the MTD.

Once the MTD is determined in Phase I, additional patients will be treated at this dose in the Phase II portion of the trial in order to define the activity and further define the toxicity of the combination at the MTD.

Patient participation in the study will comprise several periods:

The pre-treatment period includes the screening visit. After providing the written Informed Consent form to participate in the study, patients will be evaluated for eligibility during a screening period of up to 21 days (Days -21 to -1).

During the treatment period, all patients will receive Filanesib in combination with pomalidomide and dexamethasone in 28-days-cycles until progression or unacceptable toxicity.

Patients receiving the combination will be evaluated for efficacy and toxicity after the completion of each cycle.

No intra-patient escalation will be performed, that is, patients included at a given dose level during the Phase I will remain at this dose level during all treatment unless a dose reduction is required for toxicity.

All patients that discontinue treatment for any other cause different to disease progression will be evaluated in the follow-up period every two months for 1 additional year, for disease status, survival and safety (including second primary malignancies). All patients that have progressed at the end of treatment will be followed for survival and safety only (including second primary malignancy), being phone contact acceptable.

Patients will be considered to be on-study from the signature of the Informed Consent to the end of the follow-up period. Patients will be considered to be on-treatment for the duration of their treatment and in the first 30 days following treatment discontinuation. Treatment discontinuation is defined as the day of the last study drug dose administration.

Patients will receive the study combination while it is considered to be in their best interest. Specifically, treatment will continue until one or more of the following events occur:

• Disease progression.
• Unacceptable toxicity.
• Patient refusal.
• Intercurrent serious illness.
• Protocol deviation with an effect on the risk/benefit ratio of the clinical trial.
• Treatment delay > 4 weeks (except in case of clear clinical benefit, with the sponsors' approval).
• Study closure.

Inclusion Criteria:

• Age ≥18 years.

• Performance status (ECOG) ≤ 2.

• Patient is, in the Investigator's opinion, willing and able to comply with the protocol requirements.

• Patient has given voluntary written Informed Consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

• Patients previously diagnosed with MM according to the IMWG Criteria (Blood 2011) that after previous treatment with at least 2 regimens require therapy due to a relapse/progression of the disease.

• Regarding the disease history, patient must:

  • Have received 2 prior lines of therapy including bortezomib and lenalidomide.
  • Be refractory or intolerant to lenalidomide.
  • Be refractory to the last line of therapy.
  • Refractoriness to any therapy is defined as either failure to achieve minimal response with it, or development of progressive disease (PD) while on therapy or within 60 days after finishing it.
  • At least two cycles of treatment must have been received, unless PD is documented earlier.

• Only for the Phase II, patients must have measurable disease, defined as any of the following:

  • Serum monoclonal protein value ≥ 500 mg/dl.
  • Urine light chain excretion ≥ 200 mg/24 hours.
  • Abnormal serum free light chains (FLCs) ratio plus involved FLC level ≥ 10 mg/dl.

Exclusion Criteria:

• Prior therapy with Filanesib or pomalidomide.
• Non-adequate hematological or biochemical parameters as specified below:
• Hemoglobin < 8.0 g/dl.
• Platelets count < 75 x109/L without previous platelet transfusions in the last 7 days. If high bone marrow infiltration (>50%) is present, ≥ 50 x109/L platelet count is required.
• Neutrophils (ANC) <1.5 × 109/L without growth factor support (defined as no growth factor administration for at least 14 days prior to observation). If the bone marrow contains ≥ 50% plasma cells, a neutrophil count ≥1.0 × 109/L is allowed.
• Aspartate transaminase (AST): > 2.5 x the upper limit range.
• Alanine transaminase (ALT): > 2.5 x the upper limit range.
• Total bilirubin: > 2 x the upper limit range.
• Creatinine clearance: < 45 mL/min (measured or calculated with the Cockcroft and Gault formula).
• Absence of recovery from any significant non-hematological toxicity derived from previous treatments. The presence of alopecia and NCI-CTC grade < 2 symptomatic peripheral neuropathy is allowed.
• Concomitant anti-myeloma therapy, including corticosteroids at a dose greater than 10 mg/d prednisone or equivalent, within 14 days prior to Day 1 of Cycle 1.
• Pregnant or lactating women; men and women of reproductive potential who are not using highly effective contraceptive methods.
• Previous history of any other malignancy in the last five years (except basal cell carcinoma, skin epithelioma or carcinoma in situ of any site).
• Prior allogeneic bone marrow transplantation in the six prior months or active GVHD in the past month prior to cycle 1, day 1.
• Other relevant diseases or adverse clinical conditions:
• Congestive heart failure or unstable angina pectoris, myocardial infarction within 12 months before inclusion in the study.
• Uncontrolled arterial hypertension or unstable cardiac arrhythmias (i.e. requiring a change in medication within the last 3 months or a hospital admission within the past 6 months).
• History of significant neurological or psychiatric disorders.
• Active infection.
• Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis).
• Uncontrolled endocrine diseases (e.g. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).
• Patient is known to be human immunodeficiency virus (HIV) positive, Hepatitis B surface antigen-positive or active hepatitis C infection.
• Limitation of the patient's ability to comply with the treatment or follow-up protocol.