Primary Objectives:• Determine the safety and tolerability of CC-122 administered in combination with obinutuzumab.• Determine the non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of CC-122 administered in…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and tolerability will be assessed from AEs, laboratory tests, vital
signs, ECGs, Eastern Cooperative Oncology Group Performance Status (ECOG PS),
physical examinations, ophthalmologic exams, assessment of concomitant
medications, and LVEF assessments. Adverse events will be evaluated using the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE, Version 4.03) as a guide for the grading of severity.
Secondary outcome
Secondary Endpoint(s)
• Preliminary efficacy of CC-122 when administered in combination with
obinutuzumab as measured by tumor response, response duration, and
progression-free survival (PFS).
• Plasma PK parameters such as maximum observed concentration (Cmax), area
under the concentration-time curve (AUC), time to maximum concentration (Tmax),
terminal
half-life (t1/2), apparent total body clearance (CL/F) and apparent volume of
distribution
(Vz/F) for CC-122 after multiple dose administration.
Exploratory Endpoint(s)
• Target-mediated PK disposition of obinutuzumab as assessed by non-mixed
effect modeling (NONMEM) compartment analysis.
• Blood PD markers of CC-122 including modulation of Aiolos in B and T cells by
flow immunophenotyping, and other technologies to explore other biomarkers of
interest.
• Baseline and on-treatment tumor biomarkers including genetic abnormalities by
exome sequencing or other technologies, RNA expression profiling, protein
expression (eg, CRBN, Aiolos, Ikaros, cluster of CD10, BCL-6, MUM1, BCL-2, MYC,
CD68, markers of ADCC, NK cells, and other biomarkers of interest) by
immunohistochemistry or other technologies.
• Relationship between the plasma concentrations of CC-122 and PD biomarkers,
safety, and clinical endpoints.
• Relationship between PD biomarkers and clinical endpoints, including tumor
response, response duration, disease control rate and PFS.
• Relationship between genetic abnormalities and clinical endpoints including
tumor response, response duration, and PFS.
Background summary
There is no clinical data available with obintuzumab in combination with the
novel immunomodulator CC-122 that binds to cereblon. Preclinical studies
demonstrated synergy with the anti-CD20 monoclonal antibody rituximab in
combination with CC-122 in a lymphoma model and human studies in lymphoma have
demonstrated enhanced activity of rituximab in combination with IMiD drugs.
Obinutuzumab was developed to have improved direct cell killing and ADCC
compared to rituximab.
Obinutuzumab has shown single agent activity in patients with
relapsed/refractory iNHL and DLBCL. Best overall response rates at comparable
doses to be administered in this study (1,600/800 mg versus 1,000 mg) were 64%
(23% CR/CRu) for iNHL and 33% (20% CR) for DLBCL. In preliminary data from the
single-agent, dose-escalation study of CC-122 (CC-122-ST-001), 3 responses were
observed for the 5 NHL patients in the dose escalation part of the study: 1
complete response (subject with FL in the 3 mg cohort), and 2 partial responses
(2 subjects with transformed DLBCL and Mantle cell lymphoma, one each from the
3 mg and 3.5 mg cohorts).
Based on their mechanisms of action with potential for synergy and single agent
activity, evaluation of a novel treatment regimen combining CC-122 and
obinutuzumab is warranted in subjects with low grade lymphomas and
relapsed/refractory DLBCL.
Study objective
Primary Objectives:
• Determine the safety and tolerability of CC-122 administered in combination
with obinutuzumab.
• Determine the non-tolerated dose (NTD), maximum tolerated dose (MTD), and
recommended Phase 2 dose (RP2D) of CC-122 administered in combination with
obinutuzumab.
Secondary Objectives:
• Determine the preliminary efficacy of CC-122 administered in combination with
obinutuzumab.
• Characterize CC-122 pharmacokinetics (PK) in subjects coadministered CC-122
with obinutuzumab.
Exploratory Objectives:
• Explore the PK of obinutuzumab in the presence of CC-122 by population
pharmacokinetic modeling approach.
• Evaluate blood pharmacodynamic (PD) markers of CC-122 including modulation of
Aiolos in B and T cells, and potentially other biomarkers of interest.
• Evaluate baseline tumor biomarkers including genetic abnormalities, RNA
expression profiling, protein expression (eg, cereblon [CRBN], Aiolos, Ikaros,
cluster of differentiation [CD] 10, BCL-6, MUM1, BCL-2, MYC, CD68, markers of
antibody-dependent cellular cytotoxicity [ADCC]), and other biomarkers of
interest.
• Explore the effect of study treatment on tumor biomarkers, including
substrates of CRBN, RNA expression, apoptosis, cellular proliferation, and
natural killer (NK) cells.
• Explore trends between CC-122 exposure and indices of response such as
relevant PD biomarkers, efficacy endpoints and/or safety endpoints when CC-122
is given in combination with obinutuzumab and compare to historical CC-122
exposure-response data.
• Explore the relationship between PD biomarkers and clinical activity.
• To assess the safety of CC-122 formulated capsule
Study design
A Phase lb, open-label, dose escalation and expansion, clinical study of CC-122
administered in combination with obinutuzumab in subjects with relapsed or
refractory DLBCL and iNHL.
The dose escalation part (Part A) of the study will explore escalating doses of
CC-122 in combination with a fixed dose of obinutuzumab using a modified 3+3
(*rolling six*) dose escalation design to determine the MTD of CC-122 in
combination with obinutuzumab (Skolnik, 2008).
The expansion part (Part B) will further evaluate the safety and efficacy of
CC-122 administered at or below the MTD in combination with obinutuzumab in 2
cohorts of up to approximately 20 evaluable subjects each with relapsed or
refractory DLBCL and iNHL in order to determine the RP2D.
Intervention
Treatment with the investigational products (IPs) CC-122 for oral
administration and IV-infusions of Onituzumab.
In the dose escalation part (Part A), CC-122 will be administered orally once
daily (QD) starting on Day 1 for 5 consecutive days followed by 2 days off
study drug every 7 days (5/7-day schedule) in each 28-day cycle. The starting
dose level of CC-122 will be 1.0 mg QD with proposed dose escalations of 1.0 mg
increments (eg, 2.0, 3.0, and 4.0, and 4.5 mg QD on a 5/7-day schedule).
Alternate dosing schedules (eg, 21 consecutive days out of 28 days [21/28-day
schedule]) and intermediate dose levels of CC-122 may be explored. Obinutuzumab
will be administered as an intravenous (IV) infusion at a dose of 1000 mg on
Days 2, 8, and 15 of Cycle 1 and on Day 1 of Cycles 2 through 8. In addition,
subsequent subjects will be enrolled on the CC-122 formulated capsule and
evaluated for safety. The CC-122 dose will be escalated until the MTD is
established on the CC-122 formulated capsule.
In the expansion part (Part B), the selected dose and schedule of CC-122 will
be at or below the MTD established for CC-122 in combination with obinutuzumab
in the dose escalation phase and will be determined based on a review of the
study data. The obinutuzumab dose and schedule will be identical to that used
during the escalation phase.
Study burden and risks
The patients will have to come to the outpatient clinic more often for the
study and have to undergo a number of additional procedures, including extra
blood tests, eye examinations, ECGs, ECHO or MUGA, CT Scans, PET scan,
tumor/lymph node biopsies and endoscopy (if applicable). The study medication
can cause side effects, but the patients are monitored regularly.
Morris Avenue 86
Summit NJ 07901
US
Morris Avenue 86
Summit NJ 07901
US
Listed location countries
Age
Inclusion criteria
1. >= 18 years of age or older at the time of signing the informed consent
document., Entry Criteria Specific for Dose-Escalation Phase (Part A)
2. Subjects with CD20 positive, histologically or cytologically-confirmed,
DLBCL (including transformed low grade lymphoma) who have relapsed or
refractory disease following at least two prior standard treatment regimens
(eg, R-CHOP or similar first-line regimen and at least one second-line salvage
regimen) and/or ASCT in chemotherapy sensitive patients (see Protocol Section
7.2 for exceptions). , 3. Subjects with CD20 positive, histologically confirmed
(by WHO 2008 classification [Jaffe, 2009]), FL (Grade 1, 2, or 3a) or MZL who
have relapsed or refractory disease following at least one prior standard
systemic treatment regimen including systemic chemo-, immune-, or
chemoimmunotherapy., Entry Criteria Specific for Dose-Expansion Phase (Part B):
4.Subjects with CD20 positive, histologically confirmed FL (Grade 1, 2, or 3a)
who have relapsed or refractory disease following at least one prior standard
systemic treatment regimen including systemic chemo-, immune-, or
chemoimmunotherapy., Lenalidomide naïve
a. Relapsed or refractory follicular lymphoma (Grade 1, 2, or 3a) following at
least one prior standard systemic treatment regimen including systemic chemo-,
immune-, or chemoimmunotherapy with no prior exposure to lenalidomide (FL-1
cohort). In addition, subjects must have received one prior line of salvage
therapy, unless ineligible for autologous transplant.
Lenalidomide exposed
b. Relapsed or refractory follicular lymphoma (Grade 1, 2, or 3a) previously
treated with at least two cycles of lenalidomide-containing regimen (FL-2
cohort), either as a single agent or in combination, and experienced outcomes
to the lenalidomide treatment as follows:
- Early relapse after lenalidomide treatment
-Early progression after lenalidomide treatment
-Disease refractory to lenalidomide
- Lenalidomide or lenalidomide - containing regimen does not need to be the
immediate prior regimen received by the subject to be eligible for entry.,
Entry Criteria that apply to both Part A and Part B
5. Bi-dimensionally measurable disease with at least one lesion > 1.5 cm in the
transverse diameter.
- Measurable disease cannot be previously irradiated. , 6. ECOG PS of 0 to 1.
, 7. Subjects must have the following laboratory values at screening:
• Absolute Neutrophil Count (ANC) >= 1.5 x 10*9/L without growth factor support
for 7 days (14 days if subject received pegfilgrastim).
• Hemoglobin (Hgb) >= 8 g/dL.
• Platelets (plt) >= 50 x 10*9/L without transfusion for 7 days.
• Potassium within normal limits or corrected with supplements.
• AST/SGOT and ALT/SGPT <= 2.5 x Upper Limit of Normal (ULN) or <= 5.0 x ULN if
liver tumor is present.
• Serum bilirubin <=1.5 x ULN except in cases of Gilberts Syndrome, then <= 2.0
x ULN
• Estimated serum creatinine clearance of >= 60 mL/min using the Cockcroft-Gault
equation.
Exclusion criteria
1. Prior ASCT <= 3 months before first dose.
2. Prior allogeneic stem cell transplant with either standard or reduced
intensity conditioning.
3. Prior systemic cancer-directed treatments or investigational modalities <= 5
half lives or 1 month prior to starting study drugs, whichever is shorter.
4. Prior radiotherapy within 1 month prior to starting study drugs.
5. A major surgery <= 2 weeks prior to starting study drugs. Subjects must have
recovered from any effects of recent surgery or therapy that might confound the
safety evaluation of study drug.
6. Prior treatment with CC-122 or obinutuzumab (GA101).
7. History of severe allergic or anaphylactic reactions to humanized monoclonal
antibodies.
a. Allergic to any excipients in obinutuzumab.
8. Treatment-related myelodysplastic syndrome.
9. Prior history of secondary malignancies (except for basal cell or squamous
cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless
the subject has been free of the disease for >= 1 year prior to starting study
drugs.
10. Prior immunization with live virus vaccines (within 3 months prior to
starting study drug) or anticipated immunization with live virus vaccines
during the duration of the study.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003333-26-NL |
| ClinicalTrials.gov | NCT02417285 |
| CCMO | NL51241.018.14 |