A Phase I/II, Multi-center, Open-label Study to Assess the Safety, Pharmacokinetics, and Preliminary Efficacy of an Orally Available Small Molecule, CC-99282, Alone and in Combination With Anti-Lymphoma Agents in Subjects With Relapsed or Refractory Non-Hodgkin Lymphomas (R/R NHL).
Study Identifier:
CC-99282-NHL-001
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
Recruitment Complete
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Study Summary
To evaluate the safety, tolerability, and preliminary efficacy of CC-99282 alone and in combination with anti-lymphoma agents in participants with relapsed or refractory non-Hodgkin's lymphomas. To evaluate the safety and tolerability of escalating doses of CC-99282 in R/R DLBCL and/or R/R FL subjects. To determine the MTD of CC-99282 as monotherapy. To evaluate MTD in subjects with R/R DLBCL and NHL. Dose escalation: To evaluate the safety and tolerability of escalating doses of CC-99282 in relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) and/or relapsed or refractory follicular lymphoma (R/R FL) participants to determine the maximum tolerated dose (MTD) of CC-99282 as monotherapy. Dose expansion: To evaluate the safety and preliminary efficacy of single agent CC-99282 safety and preliminary efficacy of CC-99282 in combination with rituximab in participants with R/R DLBCL and R/R FL. To evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), and preliminary efficacy of single agent CC-99282 or the safety and preliminary efficacy of CC-99282 in combination with anti-lymphoma agents in participants with R/R DLBCL and NHL. Part B Cohort B will further evaluate the potential effects of food on the PK and safety of CC-99282. To report 30 mo follow up of pts with R/R FL who received GOLCA mono, and updated safety/efficacy of GOLCA + RTX from the ongoing Phase 1/2 CC-99282-NHL-001 study (NCT03930953) The efficacy-evaluable population consisted of pts completing ≥ 1 cycle of GOLCA and having baseline tumor assessment and ≥ 1 post-baseline tumor assessment or clinical progression or disease-related death. To provide extended f/u for pts with R/R FL in the Phase 1/2 CC-99282-NHL-001 study (NCT03930953). To report extended follow-up (f/u) for GOLCA ± rituximab (R) in pts with R/R FL. To provide longer follow-up in patients with R/R FL from Part B of the study
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I/II
Sex
Female & Male
Age
18+ years
Study Drug
Study Status
Indicates the current recruitment status or the expanded access status
Recruitment Complete
Requirements information
Inclusion criteria
- Subject is >or=18 years of age at the time of signing the informed consent form (ICF). Subject has a history of NHL (including DLBCL, FL, MCL, and PCNSL) with relapsed or refractory disease Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Subjects must have the following laboratory values: Absolute neutrophil count (ANC) >or= 1.5 x 109/L without growth factor support for 7 days (14 days if pegfilgastrim) Hemoglobin (Hgb) >or= 8 g/dL Platelets (plt) >or= 75 x 109/L without transfusion for 7 days Serum bilirubin or= 60 mL/min using the Cockcroft-Gault equation. Agree to follow the CC-99282 Pregnancy Prevention Plan (PPP) Part A includes pts with R/R DLBCL or follicular lymphoma (FL) who had progressed after ≥2 lines of therapy, including IMiD/CELMoD agents and chimeric antigen receptor T-cell (CAR-T) therapy, and pts with R/R DLBCL who received ≥1 line of standard therapy and are unfit for transplant. 1 The subjects were ≥18 years old when signing the informed consent form (ICF) 2 Subjects must understand and voluntarily sign the ICF prior to any study-related assessments/procedures 3 The subject is willing and able to comply with the study visit schedule and other protocol requirements 4 Subjects had a history of NHL with relapsed or refractory disease. a. For subjects with R/R DLBCL (new) and FL 3b: have received at least 2 lines of treatment in the past, or failed at least 1 line of standard treatment in the past and are not suitable for SCT. At the time of enrollment, subjects who had previously received only first-line standard therapy must be ineligible for autologous SCT. Documentation of ineligibility for SCT is required. b. For subjects with R/R DLBCL (transformed lymphoma): have received at least 2 prior lines of therapy, of which at least 1 therapy must have been received after transformation; therefore, patients must have received prior At least one DLBCL standard treatment plan, and the subject is not suitable for high-dose chemotherapy and subsequent autologous SCT. c. For R/R DLBCL and FL 3b subjects enrolled in the combined tafasitamab cohort in Part B: have received 1 to 3 systemic regimens (at least 1 anti-CD20 therapy), and are not eligible for high-dose chemotherapy and subsequent Autologous SCT. For subjects who have previously received CD19 CAR T therapy, before enrolling in the tafasitamab cohort, a biopsy after CAR T treatment is required to prove CD19 positive. d. For R/R FL subjects enrolled in the combined rituximab cohort in Part B: Previously received at least one line of rituximab-containing therapy, and met the treatment criteria based on the investigator's assessment at the time of enrollment . Class 1, 2, 3a, 3b subjects are eligible; Class 1, 2 or 3a subjects will be assigned to the Part B FL cohort, while Class 3b subjects will be assigned to the Part B DLBCL cohort. For FL class 3b subjects enrolled in the tafasitamab cohort in Part B: have received 1 to 3 systemic regimens (at least 1 anti-CD20 therapy) and are ineligible for high-dose chemotherapy and subsequent autologous SCT. e. For R/R FL subjects enrolled in the combined obinutuzumab or tazemetostat cohort in Part B: Previously received at least 2 lines of therapy and met treatment criteria based on investigator assessment at enrollment. ; Class 1, 2, or 3a subjects will be assigned to the Part B FL cohort, while Class 3b subjects will be assigned to the Part B DLBCL cohort. For FL class 3b subjects enrolled in the combination tafasitamab cohort in part B: have received 1 to 3 systemic regimens (at least 1 anti-CD20 therapy), and are not eligible for high-dose chemotherapy and subsequent autologous SCT. f. For R/R MCL subjects in Part B: Previously received at least 2 lines of therapy. Subjects must have progressed or refractory to at least one regimen containing a BTK inhibitor. g. For R/R PCNSL subjects in Part B: Previously received at least 2 lines of therapy. In addition, PCNSL subjects must meet the following criteria: Subjects have stable neurological symptoms. 5 Subjects must have measurable lesions: a. Defined as at least one FDG-affinity lesion for fluorodeoxyglucose (FDG)-affinity disease, and transected by computed tomography (CT) or magnetic resonance imaging (MRI) Surface imaging shows a two-dimensional measurable lesion, and at least one lesion has a transverse diameter > 1.5 cm, and the measurable lesion is defined according to the NHL Lugano classification (Cheson, 2014) and has not been previously irradiated b. PCNSL subjects in Part B Must have objectively measurable disease, cerebrospinal fluid (CSF) cytology (for leptomeningeal disease only), or vitreous aspiration cytology and /or retinal photograph (for ocular lymphoma, if clinically indicated) disease 6 Subjects consented to the use of formalin-fixed paraffin-embedded (FFPE) archived tumor tissue, either tumor block or sectioned/fixed specimen, if the tissue was collected within the past year and used in lieu of screening biopsy for PD. 7 For subjects participating in Part A, subjects consent and their tumors can undergo tumor biopsy or FNA during the screening period, and FNA can be performed in Cycle 1; for Part B, subjects consent and their tumors can undergo tumor biopsy or FNA during the screening period Perform paired tumor biopsies with Cycle 1 (see Sections 6.6 and 6.2.10). 8 Subjects had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. 9 Subjects must have the following laboratory values: a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L for 7 days without growth factor support (if filgrastim is used, 14 days) b. Hemoglobin (Hgb) ≥ 8 g/dL c. Platelets (plt) ≥ 75 × 109/L without blood transfusion for 7 days d. Aspartate aminotransferase/serum aspartate aminotransferase (AST/ SGOT) and alanine aminotransferase/serum alanine aminotransferase (ALT/SGPT) ≤2.5 × upper limit of normal (ULN) e. Serum bilirubin ≤1.5 × ULN, except for Gilbert syndrome ≤2.0 × ULN f. Use Cockcroft- Serum creatinine clearance ≥45 mL/min g. International Normalized Ratio (INR) <1.5 × ULN and partial thromboplastin time estimated by Gault's formula or directly from 24-hour urine collection or using the Modified Diet in Renal Disease (MDRD) formula (aPTT) <1.5 x ULN (for untreated subjects). Note: Subjects who received treatment for thromboembolic events 3 months before enrollment, as long as they are using warfarin, low molecular weight heparin or other approved therapeutic anticoagulant or antiplatelet therapy for stable anticoagulant therapy , which is qualified. 10 Subjects must not consent to donate blood while receiving CC-99282, during dosing pauses, and for at least 28 days after the last CC-99282 dose. 11 Females of childbearing potential (FCBP) must comply with pregnancy prevention program requirements, including: a. A commitment to true abstinence from heterosexual contact (must be reviewed and documented monthly), or agree to use and be able to use at least 2 effective methods of contraception ( Oral, injectable, or implantable hormonal contraceptives#; tubal ligation; intrauterine device; spermicide-containing barrier method; or partner vasectomy), must include a high-efficiency method and an additional (barrier) method , starting from signing the ICF at least 28 days before the start of CC-99282 administration and throughout the study, and at least 6 months and 2 weeks after the last dose of CC-99282, within one year after the last dose of rituximab, Within 6 months of the last dose of Tazemetostat, within 18 months of the last dose of Obinutuzumab, and within 3 months of the last dose of Tafasitamab, except for subjects receiving tazemetostat who should not be administered concomitantly with tazemetostat Hormonal contraceptives. and b. 2 negative pregnancy tests verified by the Investigator prior to initiating CC-99282 dosing: Negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at Screening (10 to 14 days prior to Cycle 1 Day 1) ) Negative serum or urine pregnancy test at the discretion of the Investigator within 24 hours prior to study treatment on Day 1 of Cycle 1 (Note, if a Screening Serum Pregnancy Test was performed within the previous 24 hours, the test may be used as Day 1 trials conducted prior to study treatment). c. Avoid pregnancy for at least 6 months and 2 weeks after the last dose of CC-99282. d. Agree to continue pregnancy tests during the study and after the end of the study treatment. The same applies to subjects who are truly abstinent and avoid heterosexual contact. e. Agree not to donate eggs while receiving CC-99282 until at least 6 months and 2 weeks after discontinuation. f. Agree not to breastfeed or provide breast milk during CC-99282 treatment until at least 6 months and 2 weeks after discontinuation. 12 Men must comply with pregnancy prevention program requirements including true abstinence* (must be reviewed monthly) or agree to use condoms (latex condoms are recommended) when having sexual contact with a pregnant woman or FCBP, and from the date of signing the ICF, in participating Avoid conception during the study, during dosing interruptions, and for at least 3 months and 2 weeks after discontinuation of CC-99282, even after successful vasectomy. a. Males must agree not to donate semen or sperm during CC-99282 treatment until at least 3 months and 2 weeks after discontinuation. b. Males with female partners of childbearing potential must use effective contraception during tazemetostat treatment and within 3 months after the last dose. 13 Subjects who are enrolled in part C food effect: (1) Subjects must agree, be able and willing to eat a standard high-fat, high-calorie diet; (2) Subjects do not eat food containing Products with caffeine or xanthenes (coffee, tea, cola, chocolate, etc.). Patients with R/R FL with ≥ 2 prior lines of therapy (≥ 1 in Part B if prior anti-CD20 therapy) were included in the study
Exclusion criteria
- Life expectancy
- Received prior systemic anti-cancer treatment (approved or investigational) = 5 half-lives or 4 weeks prior to starting CC-99282, whichever is shorter
- Is on chronic systemic immunosuppressive therapy or corticosteroids or has clinically significant graft-versus-host disease (GVHD)
- Impaired cardiac function or clinically significant cardiac disease
- Subjects who have aggressive lymphoma relapse requiring immediate cytoreductive therapy to avoid potential life-threatening consequences (eg, due to tumor location).
- Other protocol-defined inclusion/exclusion criteria apply
- Subject had prior autologous SCT
- Subject had prior allogeneic SCT with either standard or reduced intensity conditioning
- 1The subject has any serious medical condition, laboratory abnormality or mental illness that prevents him or her from participating in the study
- 2Subject has any disease (including active or uncontrolled infection) or laboratory abnormality that would place it at an unacceptable risk to participate in this study
- 3The subject suffers from any medical condition that affects the ability to interpret the study data
- 4Subject life expectancy ≤ 2 months
- 5Subject has relapsed aggressive lymphoma requiring immediate cytoreductive therapy to avoid potentially life-threatening consequences (e.g. due to tumor location)
- 6Subjects have received systemic anticancer therapy (approved or investigational) within ≤ 5 half-lives or 4 weeks (whichever is shorter) before starting the administration of the investigational drug. a. Part B tafasitamab cohort excludes patients who have previously received tafasitamab b. Part B tazemetostat cohort excludes patients who have previously received tazemetostat
- 7Subjects have previously received CAR-T or other T cell targeted therapy (approved or investigational) within ≤ 4 weeks before starting the administration of the investigational drug.
- 8Subjects have received CRBN modulating drugs (such as lenalidomide, avadomide/CC-122, pomalidomide, CC-99282) within ≤ 4 weeks before starting the drug administration of the test
- 9The subject is a pregnant or lactating woman, or intends to become pregnant during study participation
- 10Subject has disease symptomatic CNS involvement (does not apply to PCNSL subjects in Part B)
- 11Persistent diarrhea or malabsorption grade ≥2 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) despite medical treatment
- 12Peripheral neuropathy ≥ NCI CTCAE grade 2
- 13Subject is receiving chronic systemic immunosuppressive therapy or corticosteroids (such as prednisone or equivalent, not to exceed 10 mg per day in the past 14 days) or subject has clinically significant graft-versus-host disease (GVHD) . a. Stable treatment with inhaled corticosteroids is allowed b. Topical steroids are allowed for persistent cutaneous or ocular GVHD c. In Part B, corticosteroids can be used in patients with PCNSL but must be on a stable dose by Day 1 of Cycle 1 7 days
- 14Subjects with impaired cardiac function or clinically significant cardiac disease, including any of the following: a. Left ventricular ejection fraction (LVEF) <45 as determined by multiple gated acquisition scan (MUGA) or echocardiography (ECHO) % b. Left bundle branch or double bundle branch complete block c. Congenital long QT syndrome d. Sustained or clinically significant ventricular arrhythmia e. Screening period electrocardiogram (ECG) QTcF ≥ 470 ms ( Average of triplicate recordings) f. Unstable angina or myocardial infarction within ≤ 3 months prior to initiation
- 15Subjects have received autologous SCT within ≤ 3 months before starting the administration of the test drug. Unresolved treatment-related toxicity (>Grade 1) if subject received autologous SCT >3 months prior to initiation of study drug administration
- 16Subjects had received standard or reduced-dose preconditioning allogeneic SCT ≤ 6 months prior to initiation of study drug administration. If subject has received allogeneic SCT >6 months prior to initiation of investigational drug, any treatment-related toxicities are unresolved (>Grade 1)
- 17Subjects have undergone major surgery within ≤ 2 weeks before starting the administration of the test drug. Subject must have recovered from any clinically significant effects of recent surgery
- 18Received radiation therapy within 1 month before starting the trial drug administration
- 19The subject is known to be infected with human immunodeficiency virus (HIV)
- 20Subjects with known chronic active hepatitis B or C virus (HBV/HCV) infection
- twenty oneSubject has a history of concurrent second cancer requiring aggressive, ongoing systemic therapy
- twenty twoConcomitant use of potent CYP3A4/5 modulators
- twenty threeSubjects enrolled in the tazemetostat cohort received concomitant strong or mild CYP3A inducers
- twenty fourMild or asymptomatic SARS-CoV-2 infection within 10 days prior to the start of trial drug administration (i.e. C1D1), or severe/critical SARS-CoV-2 infection within 20 days. a. Acute symptoms must have resolved and, as assessed by the investigator in consultation with the medical monitor, there are no sequelae that would place the subject at increased risk of receiving study treatment
- 25Received SARS-CoV-2 vaccine within 14 days before starting the administration of the investigational drug (i.e. C1D1). For vaccines requiring more than one dose, the entire series (eg, two doses in a two-dose series) should be completed prior to C1D1, when feasible and C1D1 delay would not pose a risk to study subjects.
- 26The subject has known hypersensitivity to the investigational drug or its components (rituximab, obinutuzumab, tafasitamab, tazemetostat).
- 27For subjects enrolled in the Part B cohort who will receive either rituximab or obinutuzumab, subjects have a history of progressive multifocal leukoencephalopathy (PML).
- 28Subjects had any previous history of interstitial lung disease (ILD).
- 29The subject had an episode of non-infectious pneumonia within 3 months of starting study treatment.
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (FJD)
Madrid, Spain, 28040
Investigator
Daniel Morillo Giles
Status
Recruitment Complete
Condition(s) Treated at Site
Lymphoma