An Open-Label Study to Determine the Maximum Tolerated Dose and Evaluate the Safety and Efficacy of CEP-18770 in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- CEP-18770
- Conditions
- Multiple Myeloma
- Sponsor
- Teva Branded Pharmaceutical Products R&D, Inc.
- Enrollment
- 11
- Locations
- 8
- Primary Endpoint
- Maximum Tolerated Dose of CEP-18770
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The primary objective of the study is to determine the maximum tolerated dose (MTD) of CEP-18770 in combination with lenalidomide and dexamethasone in participants with relapsed or refractory multiple myeloma.
Detailed Description
After cycle 1, the start of treatment in each cycle may occur within a 3-day window. In addition, after cycle 2, the start of treatment in cycle 3 may be delayed by 1 week if, in the opinion of the investigator, the delay is warranted. If a participant cannot receive 75% of the planned dose for any of the 3 agents (missing more than 1 dose of CEP-18770, or more than 5 doses of lenalidomide \[either consecutively or separately\], or more than 1 dose of dexamethasone \[either consecutively or separately\]), due to a drug-related adverse event, the event will be considered a dose limiting toxicity (DLT), even if the grade of toxicity is lower than specified DLT determination. Participants will receive intravenous (IV) CEP-18770 on Days 1, 8, and 15, oral lenalidomide on days 1 through 21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment with all 3 drugs will continue for up to 12 cycles (approximately 11 months), or until disease progression or intolerable toxicities. Participants experiencing clinical benefit may continue to receive additional treatment at the investigator's discretion and following sponsor notification. In part 2 of the study, participants will receive CEP-18770 as a slow IV bolus (approximately 1 milliliter per minute) at the maximum tolerated dose on days 1, 8, and 15 of every 28-day cycle. Participants who complete or discontinue study drug treatment and whose disease has not progressed will have study visits every 7-9 weeks during follow-up until disease progression, death, or until they have been monitored for 1 year after the first administration of study drug, whichever occurs first.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The participant is a man or woman at least 18 years of age with documented multiple myeloma.
- •The participant has relapsed or progressive disease after receiving at least 1 previous chemotherapy treatment but no more than 5 previous therapies.
- •The participant has measurable disease defined as 1 of the following:
- •serum M-protein 0.5 grams (g)/deciliter (dL) or greater
- •urine M-protein 200 mg/24 hours or greater
- •The participant has a life expectancy of more than 3 months.
- •Written informed consent is obtained.
- •The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
- •The participant has adequate hepatic and renal function and hematologic assessments as specified by the study protocol
- •The participant has been independent of support with granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) for more than 1 week at the time of screening.
Exclusion Criteria
- •The participant has nonmeasurable multiple myeloma, defined as less than 0.5 g/dL M-protein in the serum, and less than 200 mg/24 hours M-protein in the urine.
- •The participant could not tolerate previous lenalidomide or low-dose dexamethasone treatment.
- •The participant had previous treatment with CEP-
- •The participant has POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy or monoclonal proliferative disorder, and skin changes \[increased skin pigment, increased body hair, thickening of the skin, whitening of the nails, etc\]).
- •The participant has plasma cell leukemia or primary amyloidosis.
- •The participant received chemotherapy with approved or investigative anticancer therapeutics within 3 weeks before the first dose of study drug.
- •The participant received radiation therapy or immunotherapy within 4 weeks or localized radiation therapy within 1 week prior to the first dose of study drug.
- •The participant had major surgery within 3 weeks before the first dose of study drug.
- •The participant has congestive heart failure (New York Heart Association Class III to IV) or had symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within the last 6 months.
- •The participant had an acute infection requiring systemic antibiotics, antiviral agents, or antifungal agents within 2 weeks before the first dose of study drug.
Arms & Interventions
CEP-18770 Dose A
Participants will receive CEP-18770 Dose A intravenously (IV) on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: CEP-18770
CEP-18770 Dose A
Participants will receive CEP-18770 Dose A intravenously (IV) on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: Lenalidomide
CEP-18770 Dose A
Participants will receive CEP-18770 Dose A intravenously (IV) on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: Dexamethasone
CEP-18770 Dose B
Participants will receive CEP-18770 Dose B IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: CEP-18770
CEP-18770 Dose B
Participants will receive CEP-18770 Dose B IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: Lenalidomide
CEP-18770 Dose B
Participants will receive CEP-18770 Dose B IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: Dexamethasone
CEP-18770 Dose C
Participants will receive CEP-18770 Dose C IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: CEP-18770
CEP-18770 Dose C
Participants will receive CEP-18770 Dose C IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: Lenalidomide
CEP-18770 Dose C
Participants will receive CEP-18770 Dose C IV on Days 1, 8, and 15 in each 28-day cycle. In addition, participants will receive a fixed dose of 25 mg oral lenalidomide on Days 1 through 21 and a fixed dose of 40 mg oral dexamethasone on Days 1, 8, 15, and 22 of each 28-day cycle.
Intervention: Dexamethasone
Outcomes
Primary Outcomes
Maximum Tolerated Dose of CEP-18770
Time Frame: Cycle 1 (28 days)
MTD was based on the assessment of dose-limiting toxicity (DLT) during cycle 1 only and was defined as the highest dose at which fewer than one-third of participants in a cohort experience DLT. A DLT was defined as any of the following drug-related toxicities occurring during Cycle 1: Hematologic adverse events (AEs) (Grade 4 hematologic AEs, Grade 3 hematologic AEs with sequelae); Grade 3 nonhematologic AEs; Neuropathy (Grade 2 neuropathy, Grade 1 neuropathy with pain, worsening grade of neuropathy or new symptoms of pain associated with neuropathy); Any other toxicity that, in the judgment of the principal investigator, was a DLT; If a participant cannot receive 75% of the planned dose for any of the 3 agents (missing \>1 dose of CEP-18770, or \>5 doses of lenalidomide, or \>1 dose of dexamethasone \[either consecutively or separately\]), due to a drug-related AE, the event was considered a DLT, even if the grade of toxicity was lower than specified DLT determination as described above.
Overall Response Rate (ORR) in Participants Treated at the (Maximum Tolerated Dose) MTD, as Assessed Using International Myeloma Working Group (IMWG) Criteria
Time Frame: From the first administration of CEP-18770 up to approximately 1.5 years
The ORR is defined as percentage of participants who achieve a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) during the study. sCR: negative immunofixation in serum and urine; disappearance of any soft tissue plasmacytomas; \< 5% plasma cells in bone marrow; normal free light chain (FLC) ratio; and absence of clonal cells in bone marrow. CR: negative immunofixation in serum and urine; disappearance of any soft tissue plasmacytomas; and \<5% plasma cells in bone marrow. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis; 90% or greater reduction in serum M-protein level and urine M-protein level less than 100 milligrams (mg)/24 hours. PR: ≥50% reduction in serum M-protein level; ≥90% reduction in 24-hour urinary M-protein level or reduction to less than 200 mg per 24 hours; and ≥50% reduction in the size of any soft tissue plasmacytomas present at baseline.
Secondary Outcomes
- Duration of Response (DOR) for Participants Treated With CEP-18770 at the MTD, as Assessed Using IMWG Criteria(From the date of first response to the date of disease progression (up to approximately 1.5 years))
- Time to Progression (TTP) for Participants Treated With CEP-18770 at the MTD, as Assessed Using IMWG Criteria(From the date of first dose of study drug to the date of disease progression (up to approximately 1.5 years))
- Maximum Observed Plasma Concentration (Cmax) of CEP-18770(Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1)
- Number of Participants With Adverse Events (AEs)(From the first administration of CEP-18770 up to approximately 1.5 years)
- Time to Reach Cmax (Tmax) of CEP-18770(Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1)
- Area Under the Plasma Concentration-Time Curve From Time 0 to t (AUC0-t) of CEP-18770(Before and immediately after end of infusion (EOI) and at approximately 2, 4, and 8 hours after the EOI on Days 1 and 15 of Cycle 1)