Phase Ib/II Study of the Efficacy and Safety of the R-CMC544/R-GEMOX Combination in Diffuse Lage B-cell Lymphoma at First or Second Relapse

A Multi-center, Phase IB/II, Open Label, Single Arm Study of Inotuzumab Ozogamicin Plus Rituximab (R-CMC544) Alternating With Gemcitabine-oxaliplatin Plus Rituximab(R-GEMOX)in Patients Aged From 18 to 80 Years With CD20 and CD22 Positive Diffuse Large B-cell Lymphoma (DLBCL) in Relapse After/Refractory to 1ST or 2ND Line Treatment, Who Are no Candidates for Autologous Transplant.

The purpose of this study is to determine the recommended dose of CMC544 administered in combination with rituximab (R-CMC544), and in alternance with rituximab, gemcitabine and oxaliplatin (R-GEMOX) in the first phase of the study. After that, efficacy and safety of this combination will be evaluated preliminarily in patients with DLBCL in relapse or refractory, who are no candidates for autologous transplant.

Study Overview

• Status: Completed
• Conditions: Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: Rituximab, CMC544, Gemcitabine and Oxaliplatine

Detailed Description

This study is a multicenter, phase Ib/II, open-label, single arm trial evaluating the efficacy and safety of R-CMC544 alternated with R-GEMOX in patients with CD20 and CD22 positive DLBCL in relapse after/refractory to 1st or 2nd line treatment, who are no candidates for autologous transplant.

The study consists of 2 phases. In part 1 (potential dose de-escalation phase) subjects will be enrolled at a fixed dose of CMC544. In case of occurrence of dose limiting toxicity (DLT), cohorts of 3 to 6 subjects will evaluate a de-escalating dose of CMC544 in combination with set doses of rituximab, gemcitabine and oxaliplatin in order to obtain the MTD or recommended dose of CMC544 in this regimen. In part 2 (dose expansion phase) further safety and preliminary efficacy data of the proposed combination will be analyzed.

All patients will receive two 56 day induction cycles of alternating R-CMC544 (given on day 1) and R-GEMOX (given on day 29 and 43). Patients who obtain CR or PR, will then go on a consolidation of another two 56 day cycles of alternating R-CMC544 (given on day 1) and R-GEMOX (given on day 29 and 43).

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Bruges, Belgium, 8000
    • AZ Sint Jan
  • Gent, Belgium, 9000
    • University Hospital Gent
  • Yvoir, Belgium
    • CHU Mont-Godinne
• France
  • Créteil, France, 94010
    • Hôpital Henri Mondor
  • Dijon, France, 21000
    • CHU de Dijon
  • Lille, France, 59037
    • CHRU de Lille
  • Lyon, France, 69495
    • CHU Lyon - Sud
  • Nantes, France, 44093
    • Chu Hotel Dieu
  • Rennes, France, 35003
    • CHU Pontchaillou
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Vandoeuvre les nancy, France, 54511
    • CHU Brabois

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically documented CD20 and CD22 positive diffuse large B-cell lymphoma, according to WHO classification. CD20 and CD22 immunophenotyping at initial diagnosis is acceptable. If such prior documentation is not available, then the immunophenotyping at relapse must be established by fine-needle aspirate or biopsy or by circulating CD20 and CD22 positive NHL cells from peripheral blood during screening. Upon registration the pathological report confirming the diagnosis, must be available
• In first or second relapse or refractory to first and/or second line treatment. Refractory is defined as having exhibited less than or PR to a prior rituximab containing regimen or having relapsed within 6 months of the last dose of a prior rituximab containing regimen.
• Measurable disease by bidimensional transverse CT scan assessment
• Not eligible for autologous transplantation.
• Previously treated with a chemotherapy regimen containing anthracyclines and rituximab.
• Aged 18 - 80 years.
• ECOG performance status 0 to 2.
• Minimum life expectancy of 3 months.
• Signed written informed consent.

Exclusion Criteria:

• Burkitt, mantle cell and T-cell lymphomas.
• Central nervous system or meningeal involvement by the lymphoma.
• Contraindication to any drug contained in the R-GEMOX combination chemotherapy.
• Treatment with any investigational drug within 30 days before the first planned cycle of chemotherapy and during the study.
• Nitrosurea or mitomycin C administration within 6 weeks prior to study start.
• Major debulking surgery within 3 weeks of treatment.
• Any of the following lab abnormalities (unless related to the lymphoma or bone marrow infiltration):

Absolute neutrophil count (ANC) < 1.500/µL (1,5.109/L).

Platelet count < 100.000/µL (100.109/L).

Creatinin level > 150 µmol/L (1,7 mg/dL) or 1,5 - 2,0x ULN.

Total bilirubin level > 30 µmol/L (1,8 mg/dL) or 1,5x ULN.

Serum AST/SGOT or ALT/SGPT >2,5x ULN.

• Documented infection with HIV, active hepatitis B or C infection.
• Any serious active disease or co-morbid medical condition that, according to the investigator's decision, will substantially increase the risk associated with the subject's participation in the study. Prior history of malignancies other than lymphoma with the exception of non-melanoma skin tumors (basal cell or squamous cell carcinoma of the skin) or stage 0 (in situ) cervical carcinoma unless the subject has been disease-free for 5 or more years..
• LVEF less than 50% (measured by echocardiography or scintigraphy).
• Previous myocardial infarction or pulmonary hypertension within 6 months before the first dose of investigational product.
• Congestive heart failure NYHA stage III or IV
• Known chronic liver disease (eg. Cirrhosis) or suspected alcohol abuse.
• Pregnant or lactating females
• Men and women who are biologically capable of having children not willing to use an adequate method of birth control during the study and up to 18 months after the last dose of investigational product.
• Adult patient unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: R-CMC544 and R-GEMOX; Treatment with R-CMC544 and R-GEMOX	Drug: Rituximab, CMC544, Gemcitabine and Oxaliplatine; 2 cycles of induction of 56 days each, starting with the administration of R-CMC544 on day 1, followed by the administration of R-GEMOX on day 29 and 43. 2 cycles of consolidation of 56 days each, starting with the administration of R-CMC544 on day 1, followed by the administration of R-GEMOX on day 29 and 43.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the Recommended Dose of R-CMC544	Determination of recommended dose will be based on safety parameters and particularly on incidence of DLTs	Up to 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OVERALL RESPONSE RATE	Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 1999 and 2007). Patient is defined as a responder if he/she has a complete response (CR) or partial response (PR) at the end of treatment. A descriptive analysis will also be performed considering as non-responders all patients who relapsed or died during treatment phase even if they were prematurely withdrawn as responder	Up to 32 weeks
PROGRESSION-FREE SURVIVAL	Progression-Free Survival will be measured from the date of inclusion to the date of first documented disease progression, relapse or death from any cause. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.	Up to 3.5 years
EVENT FREE SURVIVAL	Event-Free Survival will be measured from the date of inclusion to the date of first documented disease progression, relapse, initiation of new anti-lymphoma therapy or death from any cause. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.	Up to 3.5 years
OVERALL SURVIVAL	Overall survival will be measured from the date of inclusion to the date of death from any cause. Patients who are alive at the time of analysis will be censored at the date of the last contact.	Up to 3.5 years
COMPLETE RESPONSE RATE	Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 2007)). Patient without response assessment (due to whatever reason) will be considered as nonresponder.	30 or 32 weeks (depending on induction cycle length)

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Collaborators: Pfizer
• Investigators: Study Chair: Fritz OFFNER, MD, Lymphoma Study Association; Study Chair: Corinne HAIOUN, PhD, Lymphoma Study Association

Publications and helpful links

Helpful Links

• LYSA (Lymphoma Study Association) website

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (ACTUAL): August 1, 2014
• Study Completion (ACTUAL): March 1, 2016

Study Registration Dates

• First Submitted: March 20, 2012
• First Submitted That Met QC Criteria: March 23, 2012
• First Posted (ESTIMATE): March 26, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): May 23, 2016
• Last Update Submitted That Met QC Criteria: May 20, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Gemcitabine; Oxaliplatin; Rituximab; Inotuzumab Ozogamicin
• Other Study ID Numbers: CMC-R-GEMOX; 2011-003849-18 (EUDRACT_NUMBER)