Lymphoma, Non-Hodgkin, Neoplasms
Conditions
Keywords
Non-Hodgkin's Lymphomas, Safety, Efficacy, CC-90010, Solid Tumors, Relapsed/Refractory
Brief summary
Study CC-90010-ST-001 is an open-label, Phase 1a, dose escalation and expansion, First-in-human (FIH) clinical study of CC-90010 in subjects with advanced or unresectable solid tumors and relapsed and/or refractory advanced Non-Hodgkin's lymphoma (NHL). The dose escalation part (Part A) of the study will explore escalating oral doses of CC-90010 to estimate the maximum tolerated dose (MTD) of CC-90010. The expansion part (Part B) will further evaluate the safety and efficacy of CC-90010 administered at or below the MTD in the following cohorts: Cohort 1: relapsed and/or refractory DLBCL approximately 20-25 evaluable subjects at 45 mg CC-90010 4-days-on/24-days-off in each 28-day cycle Cohort 2: advanced BCC -enrollment stopped due to recruitment challenges Cohort 3: relapsed and/or refractory DLBCL -approximately 15 evaluable subjects at 30mg CC-90010 3-dayson/11-days-offin each 28-day cycle. The enrollment of subjects with R/R DLBCL in Cohort 1 and Cohort 3 was closed due to Company's strategic decision and not due to any safety concern or lack of preliminary antitumor efficacy. The food effect assessment (Part C, Spain only) will evaluate the impact of food on CC-90010 when administered at the RP2D of 45 mg 4-days-on/24-days-off (180 mg per 28-day cycle), by comparison of the PK parameters following fasted and fed (high-fat, high-calorie meal) conditions.
Detailed description
Parts A, B and C will consist of 3 periods: Screening, Treatment and Follow-up. Screening Period: The Screening Period starts 28 days (± 3 days) prior to first dose of CC-90010. The informed document (ICD) must be signed and dated by the subject and the administering staff prior to the start of any other study procedures. All screening tests and procedures must be completed within the 28 days (±3 days) prior to the first dose of CC-90010. Treatment Period: During the Treatment Period, CC-90010 was initially administered orally once daily for 3 consecutive days followed by 4 consecutive days off drug every week (3/7-days schedule) in each 28-day cycle in Part A. Alternative dosing schedules (eg, 2-days-on/5-days- off each week, 3-days-on/4-days-off every other week, 4-days on/24 days off) may be evaluated one dosing schedule at a time or ≥ 2 dosing schedules given in parallel, based on the review of available safety, PK, pharmacodynamic (PD), and efficacy data by the SRC. Following completion of dose escalation in Part A, selected expansion cohorts will receive CC-90010 in Part B. The SRC determined the RP2D for Part B to be 45 mg CC-90010 given once daily for 4 consecutive days on followed by 24 consecutive days off (4-days-on/24-days-off) in each 28-day cycle. There are 3 cohorts in Part B expansion. A cohort of up to approximately 20-25 subjects with relapsed and/or refractory DLBCL (Cohort 1) enrolled at the RP2D.. Enrollment in advanced BCC (Cohort 2) will be stopped due to recruitment challenges. An additional cohort of approximately 15 evaluable subjects with R/R DLBCL (Cohort 3) will be enrolled under an alternative dosing regimen of 30 mg CC-90010 3days-on/11-days off in each 28-day cycle. The enrollment of subjects with R/R DLBCL in Cohort 1 and Cohort 3 was closed due to Company's strategic decision and not due to any safety concern or lack of preliminary antitumor efficacy. The food effect assessment (Part C, Spain only) will evaluate the impact of food on CC-90010 when administered at the RP2D of 45 mg 4-days-on/24-days-off, by comparison of PK parameters following fasted and fed (high-fat, high-calorie meal) conditions in approximately 24 subjects with advanced solid tumors. Follow-up Period: In the Follow-up Period, subjects will be followed for 28 days (± 3 days) after the last dose of CC-90010 for safety. After the Safety Follow-up visit, all subjects will be followed every subsequent 3 months (± 2 weeks) for survival follow-up for up until 2 years or until death, lost to follow-up, or the End of Trial, whichever occurs first.
Interventions
DRUGCC-90010
CC-90010 is an oral, potent and reversible inhibitor of the epigenetic target bromodomain and extra-terminal (BET) proteins.
Sponsors
Celgene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age = or \> 18 years. 2. For subjects enrolling in food-effect assessment (Part C) only: a. Subject must agree and be willing to consume a standard high-fat, high-calorie meal. b. Subject must be willing to refrain from caffeine or xanthene-containing products (coffee, tea, cola, chocolate, etc.) for 48 hours prior to dosing on Cycle 1 Day 4 and Cycle 2 Day 4 and up to 24 hours post dose. 3. Subjects with histological or cytological confirmation of either: 1. In Part A, advanced or unresectable solid tumors or advanced relapsed and/or refractory Non-Hodgkin lymphoma (ie, Diffuse large B-cell lymphoma and Follicular lymphoma or Marginal zone lymphoma) including those who have progressed on (or not been able to tolerate due to medical comorbidities or unacceptable toxicity) standard anticancer therapy or for whom no other approved conventional therapy exists. 2. In Part B dose expansion, - Cohorts 1 and 3: relapsed and/or refractory DLBCL following at least 2 prior lines of therapy (e.g. have failed at least one line of standard therapy and have received at least one prior line of salvage therapy) OR have failed at least one prior line of standard therapy and are not eligible for autologous stem cell transplant (ASCT) or have declined ASCT; transformed lymphoma following chemotherapy for lower grade lymphoma and at least two standard treatment regimen for DLBCL. Subjects with two or more lines of systemic therapy must have been treated with and have lack of response after chimeric antigen receptor (CAR) T-cell therapy, if such therapy is available, OR be ineligible for CAR T-cell therapy at the time of enrollment, OR subject declined CAR T-cell therapy. \- Cohort 2: advanced basal cell carcinoma including those who have progressed on (or not been able to tolerate due to medicalcomorbidities or unacceptable toxicity) standard anticancer therapy or for whom no other approved conventional therapy exists. In Part C, advanced or unresectable solid tumors including those who have progressed on (or not been able to tolerate due to medical comorbidities or unacceptable toxicity) standard anticancer therapy or for whom no other approved conventional therapy exist 4. At least one site of measurable disease for subjects with solid tumors; bi-dimensionally measurable disease on cross sectional imaging with at least one lesion \>1.5 cm for subjects with NHL. For subjects with rare malignancies evaluable disease can be considered. 5. Tumor biopsies whenever safe and feasible will be collected in Part A, except for subjects with GBM. Subject consents to mandatory tumor biopsies (Screening and on treatment) in Part B. In exceptional circumstances an exemption waiver may be granted by the Sponsor for this criterion 6. ECOG PS of 0 to 1. 7. Females of childbearing potential (FCBP)1 must: • Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner), one of which must be barrier, from signing the ICD, throughout the study (including dose interruptions), and for up to 6 months and 16 days following the last dose of CC-90010; and * Avoid conceiving for 6 months and 16 days after the last dose of CC-0010. * Agree to not donate oocytes while receiving CC-90010 and for 6 months and 16 days after the last dose of CC-90010. 8. Males must practice true abstinence2 (which must be reviewed on a monthly basis) or agree to use a condom (a latex condom is recommended) during sexual contact with a pregnant female or a FCBP and will avoid conceiving from signing the ICD, while participating in the study, during dose interruptions, and for at least 106 days following CC-90010 discontinuation, even if he has undergone a successful vasectomy. Additionally, subjects must not donate sperm during this same time period.
Exclusion criteria
Principal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events (AEs) | Up to 7 years | Number of participants with adverse events |
| Dose Limiting Toxicities (DLTs) | Up to 7 years | A DLT is defined as any of the toxicities described in the protocol occurring within the DLT assessment unless the event can clearly be determined to be unrelated to CC-90010 |
| Maximum tolerated dose (MTD) | Up to 7 years | The MTD is the highest dose that causes DLTs in not more than 33% of the subjects treated with CC-90010 in the first cycle with at least 6 evaluable subjects treated at this dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of stable disease | Up to 7 years | For subjects with best response of SD, duration of SD is measured from the first dose date until the criteria for progression are met |
| Progression-free survival (PFS) | Up to 7 years | Is defined as the time from the first dose of CC-90010 to the first occurrence of disease progression or death from any cause. |
| Overall survival | Up to 7 years | Is measured as the time from the first dose of CC-90010 to death due to any cause. |
| Pharmacokinetic- Cmax | Up to 7 years | Maximum observed plasma concentration on first and last day of dosing within a cycle |
| Pharmacokinetic- AUC | Up to 7 years | Area under the plasma concentration time-curve on first and last day of dosing within a cycle |
| Pharmacokinetic- Tmax | Up to 7 years | Time to maximum plasma concentration on first and last day of dosing within a cycle |
| Clinical benefit rate (CBR) | Up to 7 years | Is defined as tumor responses (as assessed by the Investigators) of complete response (CR), partial response (PR) and stable disease (SD) (SD of ≥ 4 months duration). |
| Apparent Clearance | Up to 7 years | Apparent total systemic clearance to be estimated following the last dose in cycle 1 |
| Apparent Volume of Distribution | Up to 7 years | Apparent steady state volume of distribution to be estimated following the last dose in cycle 1 |
| Pharmacokinetic- AUClast | Up to 7 years | Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration |
| Pharmacokinetic- AUC0-24 | Up to 7 years | Area under the plasma concentration-time curve calculated from time zero to 24 hours |
| Pharmacokinetic- AUC0-∞ | Up to 7 years | Area under the concentration-time curve calculated from time zero to infinity |
| Pharmacokinetic- t1/2 | Up to 7 years | Terminal half-life on last day of dosing within a cycle |
| Objective response rate (ORR) | Up to 7 years | Is defined as the percent of subjects whose best response is CR or PR. |
| Duration of Response Rate | Up to 7 years | Is measured from the time when criteria for CR/PR are first met (whichever is first recorded) until the first date at which progressive disease is objectively documented |
Countries
France, Italy, Japan, Spain
Outcome results
None listed