A Phase 1a/1b, Multi-center, Open-label, Dose Finding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the Pleiotropic Pathway Modifier CC-122 Administered Orally to Subjects With Advanced Solid Tumors, Non-Hodgkin's Lymphoma, or Multiple Myeloma.
Overview
- Phase
- Phase 1
- Intervention
- CC-122
- Conditions
- Multiple Myeloma
- Sponsor
- Celgene
- Enrollment
- 271
- Locations
- 39
- Primary Endpoint
- Pharmacokinetics- CL/F
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The main purpose of this first in human study with CC-122 is to assess the safety and action of a new class of experimental drug (Pleiotropic Pathway Modulator) in patients with advanced tumors unresponsive to standard therapies and to determine the appropriate dosing level and regimen for later-stage clinical trials.
Detailed Description
This trial is enrolling additional Multiple Myeloma (MM) subjects in a separate cohort defined as MM-2 to evaluate tolerability, safety and preliminary efficacy of CC-122 formulated capsule alone or in combination with DEX on intermittent dosing schedule (5 of 7 days of the week) in Pomalidomide-naïve subjects. Preliminary efficacy data in Multiple Myeloma subjects, warrants further exploration of CC-122 in MM on intermittent schedules to assess if dose intensity and tolerability can be improved. Initially, patients will be treated with oral CC-122 for one month. During this time, various tests (involving blood and urine collections, ECGs, etc) will be performed. Those whose tumors stabilize or regress may continue receiving treatment for as long as they benefit from CC-122. Different dose levels of CC-122 will be tested in a dose-rising study design.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
- •Men and women, 18 years or older, with histologically or cytologically-confirmed, advanced solid tumors, Non-Hodgkin Lymphona (NHL), Multiple Myloma (MM), or advanced unresectable solid tumors limited to the tumor types below.
- •Subjects who have progressed on (or not been able to tolerate) standard anticancer therapy or for whom no standard anticancer therapy exists. Must have disease that is objectively measurable
- •Measurable disease criteria:
- •Subjects with Glioblastoma multiforme (GBM) do not have to have objectively measurable disease at entry.
- •For MM, Diffuse large B-cell lymphoma (DLBCL): Subjects must have disease that is objectively measurable, measurable levels of myeloma paraprotein in serum (\> 0.5 g/dL) or urine (\> 0.2 g excreted in a 24-hour collection sample) for MM and measurable disease by Internatonal Working Group (IWG) for NHL (with at least one measurable lesion's longest diameter ≥ 2cm).
- •For Primary Central Nervous System (CNS) Lymphoma (PCNSL): Subjects must have disease that is objectively measurable by International Workshop to Standardize Baseline Evaluation and Response Criteria in Primary CNS Lymphoma, Cerebrospinal Fluid (CSF) cytology (in case of leptomeningeal only disease), or vitreal aspiration cytology and/or retinal photographs (in case of ocular lymphoma).
- •Tumor specific inclusion criteria:
- •DLBCL-2 cohort:
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤
Exclusion Criteria
- •History of other carcinomas within the last 5 years except cured non-melanoma skin cancer, curatively treated in-situ cervical cancer, or localized prostate cancer with a current Prostate-specific antigen (PSA) of \<1.0 mg/dL on 2 evaluations at least 3 months apart; the most recent evaluation must be no more than 4 weeks prior to Day 1 of the study drug, or other malignancies that were completely resected or treated Stage 1/2 lesions currently in complete remission.
- •Symptomatic central nervous system metastases (excluding Glioblastoma multiforrme (GBM) and Primary Central Nervous System Lymphoma (PCNSL). Subjects with brain metastases that have been previously treated and are stable for 6 weeks are allowed.
- •Known symptomatic acute or chronic pancreatitis.
- •Any peripheral neuropathy ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade
- •Persistent diarrhea or malabsorption ≥ NCI CTCAE grade 2, despite medical management.
- •Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
- •left ventricular ejection fraction (LVEF) \< 45% as determined by multigated acquisition (MUGA) scan or echocardiography (ECHO).
- •Complete left bundle branch, or bifasicular block.
- •Congenital long QT syndrome.
- •Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation.
Arms & Interventions
CC-122 MM-2
A new MM cohort (MM-2) will be enrolled in order to evaluate tolerability, safety and preliminary efficacy of the CC-122 formulated capsule given on an intermittent schedule (5/7 days per week) in 2 parallel dose escalation cohorts (MM-2a and MM-2b, respectively) (DEX) in Pomalidomide naïve subjects
Intervention: CC-122
CC-122- DLBCL-2
A new DLBCL cohort (DLBCL-2) in order to evaluate intermittent schedules of CC-122 (5 continuous days out of 7 days per week \[5/7 days\] and/or 21 continuous days out of 28 days per cycle \[21/28 days\]). Doses to be explored include 4 mg and 5 mg on an intermittent schedule using the 3+3 design described in Part A in order to establish an MTD for the intermittent dosing schedules. Following dose escalation, one or more intermittent dosing schedules may be expanded at or below the new intermittent schedule MTD in at least 20 total subjects per dosing schedule.
Intervention: CC-122
CC-122- GBM-2
A new GBM cohort (GBM-2) in order to evaluate doses of CC-122 above the 3 mg QD MTD determined in all comers in Part A. CC-122 dose will increase in 1 mg increments starting with 4 mg daily on a continuous schedule using the 3+3 design described in Part A in order to establish an MTD specific for GBM subjects. Following dose escalation, the cohort will be expanded at or below the new MTD in up to 20 total subjects.
Intervention: CC-122
Primary Central Nervous System Lymphoma (PCNSL)
During dose expansion of selected intermittent schedules, an additional cohort of up to 10 subjects with PCNSL will also be explored at the same dose and schedule as DLBCL to confirm some safety and preliminary efficacy signal
Intervention: CC-122
Outcomes
Primary Outcomes
Pharmacokinetics- CL/F
Time Frame: Up to day 22
Apparent total body clearance
Pharmacokinetics- Vz/F
Time Frame: Up to day 22
Apparent volume of distribution
Maximum Tolerated Dose (MTD)
Time Frame: Up to day 28
Is defined as the last dose level below the NTD with ≤1 out of 6 evaluable subjects with DLT) during Cycle (C) 1.
Dose-Limiting Toxicity (DLT)
Time Frame: Up to approximately Day 28
Dose-limiting toxicities (DLTs) will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE): * A clinically relevant AE that is suspected to be related to CC-122 and starts ≤ 30 days of first dose (Cycle 1) and ≥ grade (Gr) 3 except for Alopecia, Gr3 rash of the acneiform or maculopapular type \< 4 daysduration , Gr 3 diarrhea or vomiting lasting\< 72 hours * Clinically relevant laboratory abnormality suspected to be related to CC-122 and that commences within 30 days of first dose and ≥ Gr3. * Hematological toxicities as follows: Any febrile neutropenia (NP), Gr4 NP \> 7 days, Gr 4 thrombocytopenia \> 24 hours, Any Gr 3/4 thrombocytopenia with clinically significant bleeding. * Gr 4 liver function tests (LFTs) or Gr 3 ALT with ≥ Gr2 bilirubin * Any AE suspected to be CC-122 related and necessitating dose reduction during Cycle 1.
Pharmacokinetics- Cmax
Time Frame: Up to day 22
Maximum observed concentration in plasma (Cmax)
Pharmacokinetics- AUC
Time Frame: Up to day 22
Area under the concentration-time curve
Pharmacokinetics- tmax
Time Frame: Up to day 22
Time to maximum concentration
Pharmacokinetics- t1/2
Time Frame: Up to day 22
Terminal half-life
Non-tolerated dose (NTD)
Time Frame: Up to day 28
Is defined as the dose level at which ≥2 out of 6 evaluable subjects in any dose cohort with DLT.
Secondary Outcomes
- Response Rate(up to approximately 6 months)
- 6-month progression free survival (PFS) rate for GBM chort(Up to approximately 6 months)
- Tissue concentration of CC-122(up to approximately 6 months)