Study Comparing Inotuzumab Ozogamicin In Combination With Rituximab Versus Defined Investigator's Choice In Follicular Non-Hodgkin's Lymphoma (NHL)

An Open-label, Randomized, Phase 3 Study Of Inotuzumab Ozogamicin (Cmc-544) Administered In Combination With Rituximab Compared To A Defined Investigator's Choice Therapy In Subjects With Relapsed Or Refractory, Cd22- Positive, Follicular B-cell Non Hodgkin's Lymphoma

This protocol is designed to assess the efficacy and safety of inotuzumab ozogamicin given with rituximab compared to a defined investigator's choice therapy. Subjects will be randomized to one of these two arms of the study.

Study Overview

• Status: Terminated
• Conditions: Lymphoma, Follicular
• Intervention / Treatment: Drug: inotuzumab ozogamicin; Drug: rituximab; Drug: rituximab; Drug: cyclophosphamide; Drug: vincristine; Drug: prednisone/prednisolone; Drug: mitoxantrone; Drug: fludarabine; Drug: dexamethasone

Detailed Description

On January 14th 2009, enrollment in the study was discontinued because of poor enrollment and because it was unlikely that the study would meet the estimated enrollment of approximately 978 subjects. The decision was not prompted by the identification of any safety signals in this or other studies. Active treatment and follow-up of the already enrolled subjects was continued. On July, 22th 2010 , the study was amended to shorten the long-term follow-up to one year after active treatment.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Santa FE
    • Rosario, Santa FE, Argentina, S2000AYW
      • Centro de Transplantes de medula Osea de Rosario, CETRAMOR
• Belgium
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Wilrijk, Belgium, 2610
    • Oncologisch Centrum GZA - Location St. Augustinus
• Canada
  • Quebec, Canada, G1J 1Z4
    • C.H.A. Enfant-Jesus
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CHUS-Hopital Fleurimont
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
  • NEW Territories
    • Shatin, NEW Territories, Hong Kong
      • Prince of Wales Hospital
• India
  • Maharashtra
    • Pune, Maharashtra, India, 411001
      • Jehangir Clinical Development Centre
    • Pune, Maharashtra, India, 411004
      • MMF Joshi Hospital and Ratna Memorial Hospital
  • WEST Bengal
    • Kolkata, WEST Bengal, India, 700053
      • B. P. Poddar Hospital and Medical Research Ltd.
• Italy
  • Pavia, Italy, 27100
    • Divisione di Ematologia - Fondazione IRCCS Policlinico San Matteo
• Korea, Republic of
  • Seoul, Korea, Republic of, 120-752
    • Yonsei University Health System-Severance Hospital
• Mexico
  • Nuevo LEON
    • Monterrey, Nuevo LEON, Mexico, 64460
      • Hospital Universitario de Nuevo León
• Poland
  • Warszawa, Poland, 02-776
    • Instytut Hematologii i Transfuzjologii
• Portugal
  • Coimbra, Portugal, 3000-075
    • Hospitais da universidade de Coimbra
• Russian Federation
  • Moscow, Russian Federation, 120110
    • Moscow Regional Research Clinical Institute named after Vladimirsky
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2193
      • Wits Donald Gordon Clinical Trial Site
• Spain
  • Barcelona, Spain, 08041
    • Hospital Santa Creu i Sant Pau
  • Madrid, Spain, 28006
    • Hospital de la Princesa
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro
• United States
  • California
    • Mission Hills, California, United States, 91345
      • Facey Medical Group
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Deaconess Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • The Harry & Jeanette Weinberg Cancer Inst at Franklin Square
  • Michigan
    • Novi, Michigan, United States, 48374
      • Newland Medical Associates
    • Southfield, Michigan, United States, 48075
      • Newland Medical Associates, PC
  • Minnesota
    • Saint Louis Park, Minnesota, United States, 55426
      • Park Nicollet Frauenshuh Cancer Center
  • Mississippi
    • Columbus, Mississippi, United States, 39706
      • Hematology and Oncology Associates
    • Corinth, Mississippi, United States, 38834
      • Hematology and Oncology Associates
    • Tupelo, Mississippi, United States, 38801
      • Hematology and Oncology Associates at Bridgepoint
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Hackensack, New Jersey, United States, 07601
      • The Cancer Center at Hackensack University Medical Center
    • Morristown, New Jersey, United States, 07960
      • Hematology Oncology Associates of Northern New Jersy
  • New York
    • Armonk, New York, United States, 10504
      • Advanced Oncology Associates
    • Bronx, New York, United States, 10461
      • Avi Einzing, MD
    • New Rochelle, New York, United States, 10801
      • Advanced Oncology Associates
    • Pomona, New York, United States, 10970
      • Marc Zimmerman, MD
  • Washington
    • Wenatchee, Washington, United States, 98801
      • Wenatchee Valley Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with a diagnosis of CD20 and CD22-positive, follicular lymphoma, who have received 1 or 2 prior regimens, at least 1 of which should have contained administration of rituximab (either as a single agent or in combination).
• Age 18 years or older.
• ECOG performance status <= 2.
• ANC >= 1.5 x 10^9/L (1500/mL) and platelets >= 75 x 10^9/L (75,000/mL), serum creatinine <= 1.5 x ULN and urine protein to creatinine ratio of <= 0.5, total bilirubin <= 1.5 x ULN, AST and ALT <= 2.5 x ULN.
• At least 1 measurable disease lesion that is >= 1.5 cm x 1.5 cm by CT or MRI, in an area of no prior radiation therapy, or documented progression in an area that was previously irradiated.

Exclusion Criteria:

• Subjects with clinical evidence of transformation to a more aggressive subtype of lymphoma or grade 3b follicular lymphoma.
• Subjects whose disease is rituximab refractory, meaning that they did not have a CR or PR, or that they experienced disease progression within 6 months from the initiation of the rituximab or rituximab containing treatment regimen administered immediately preceding study enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; Subjects will receive rituximab intravenously at a dose level of 375 mg/m² on day 1 of each cycle followed by inotuzumab ozogamicin administered intravenously at a dose level of 1.8 mg/m2 on day 2. The sequence will be repeated every 28 days.	Drug: inotuzumab ozogamicin; IV administration, 1.8mg/m² on day 2 of each cycle every 28 days, for up to 8 cycles.; Drug: rituximab; IV administration, 375 mg/m² on day 1 of each cycle every 28 days, for up to 8 cycles.; Drug: rituximab; intravenous rituximab at a dose of 375 mg/m2 on day 1
Active Comparator: B; Subjects will receive the investigator's choice from the following rituximab-containing regimens: R-CVP or R-FND. The investigator's choice of therapy will be administered every 21 days. Dosing for R-CVP will be intravenous rituximab at a dose of 375 mg/m2 on day 1, intravenous cyclophosphamide at a dose of 750 mg/m2 on day 1, intravenous vincristine at a dose of 1.4 mg/m2 (not to exceed 2 mg) on day 1, and oral prednisone/prednisolone at a dose of 40 mg/m2 on days 1 through 5. Dosing for R-FND will be as follows: rituximab 375 mg/m2 intravenous on day 1, mitoxantrone 10 mg/m2 intravenous on day 2, fludarabine 25 mg/m2 intravenous on days 2 through 4 and oral dexamethasone 20 mg/day on days 1-5.	Drug: rituximab; IV administration, 375 mg/m² on day 1 of each cycle every 28 days, for up to 8 cycles.; Drug: rituximab; intravenous rituximab at a dose of 375 mg/m2 on day 1; Drug: cyclophosphamide; intravenous cyclophosphamide at a dose of 750 mg/m2 on day 1; Drug: vincristine; intravenous vincristine at a dose of 1.4 mg/m2 (not to exceed 2 mg) on day 1; Drug: prednisone/prednisolone; oral prednisone/prednisolone at a dose of 40 mg/m2 on days 1 through 5; Drug: mitoxantrone; mitoxantrone 10 mg/m2 intravenous on day 2; Drug: fludarabine; fludarabine 25 mg/m2 intravenous on days 2 through 4; Drug: dexamethasone; oral dexamethasone 20 mg/day on days 1-5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	PFS was defined as the time from randomization to disease progression or death due to any cause, whichever occurred first, censored at the last tumor evaluation date. PFS calculated as (Months) = (first event date minus randomization date plus 1) divided by 30.44.	Baseline until disease progression or death or up to 1 year after last dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Objective Response (OR)	OR was based on assessment of complete response(CR),unconfirmed CR(Cru),partial response(PR) as per International Response Criteria for Non-Hodgkin's Lymphoma.Confirmed response=response persists on repeat imaging at least 4 weeks after initial response.CR=complete disappearance of all detectable clinical/radiographic evidence of disease,lymph nodes regressed to normal size [at least 1.5 centimeter(cm) or less],spleen regressed,not palpable on physical examination,bone marrow infiltrate cleared on repeat aspiration/biopsy.PR=at least 50 percent (%) decrease in sum of product diameters of 6 greatest dominant nodes,no increase in other nodes,liver/spleen,no new sites of disease. CRu=residual lymph node greater than 1.5 cm in transverse diameter that has regressed more than 75% in product diameter.Individual nodes previously confluent,regressed more than 75% in product diameters.Indeterminate bone marrow (increased number/size of lymph aggregates without cytologic/architectural atypia).	Baseline, every 6 to 12 weeks during treatment period, end of treatment (EOT) (42 days after last dose), every 12 weeks during follow-up for up to 1 year after the last dose of study drug
Overall Survival Probability at Months 6, 12 and 24	Overall survival was defined as the time from randomization to death due to any cause, censoring at the date of last contact or the end of the study. Participants who withdrew or lost to follow-up from study without having death documented were censored at the date of last contact. Kaplan-Meier estimates of the probability of survival at 6, 12 and 24 months was used to estimate the survival function.	Baseline up to Month 6, 12, 24
Pharmacokinetics of Inotuzumab Ozogamicin in Combination With Rituximab		0, 1, 168 hours on Cycle 1, 2; 0, 1, 2, 168 hours on Cycle 3, 4

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinically Significant Change From Baseline in QT Interval Findings	Assessments of QT interval was performed only in rituximab + inotuzumab ozogamicinin group. QT interval corrected using Fridericia's formula (QTcF) and Bazett's formula (QTcB) was analyzed as per common terminology criteria for adverse events (CTCAE) version 3.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening or disabling AE, Grade 5 = death related to AE. Number of participants with change in CTCAE grading at post-baseline time point compared to the baseline were presented. The post-baseline value was defined as the maximum grade after the first dose date on or before the end of treatment.	Baseline up to 42 days post-treatment
Number of Participants With Grade 3 or 4 Treatment Emergent Adverse Events (TEAEs)	AE=any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. TEAE=between first dose of study drug and up to 42 days after last dose that were absent before treatment or that worsened relative to pretreatment state.	Baseline up to 42 days post-treatment
Number of Participants With Clinically Significant Change From Baseline in Laboratory Findings	Criteria for laboratory test abnormality: Blood Chemistry (alkaline phosphatase [greater than{>}5*upper limit of normal {ULN}, calcium [less than {<}1.75 millimole per liter {mmol/L}, creatinine [>3*ULN], glucose [>13.9 mmol/L], phosphorous [<0.6 mmol/L], potassium [<3 mmol/L], aspartate transaminase [>5.0*ULN], total bilirubin [>3*ULN]), Coagulation (international normalized ratio [>2*ULN]), Hematology (hemoglobin [<80 grams/Liter], lymphocytes [<0.5*10^9/L], absolute neutrophil count [<1*10^9/L], platelet count [<50*10^9/L], WBC [<2.0*10^9/L]).	Baseline up to 42 days post-treatment, disease follow up (every 12 weeks for a minimum of 1 year and up to 2 years)
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Criteria for determining significant change from baseline in vital signs abnormalities: heart rate value of <40 beats per minute and value >150 beats per minute, systolic blood pressure (SBP) of <80 or >210 millimeter of mercury (mmHg), diastolic blood pressure (DBP) of <40 or >130 mmHg, temperature <32 or >40 degree centigrade, and body weight>=10% increase or decrease of body weight in kilogram (kg).	Baseline up to 42 days post-treatment, disease follow up (every 12 weeks for a minimum of 1 year and up to 2 years)

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: UCB Pharma

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2007
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: November 21, 2007
• First Submitted That Met QC Criteria: November 23, 2007
• First Posted (Estimate): November 26, 2007

Study Record Updates

• Last Update Posted (Actual): January 9, 2018
• Last Update Submitted That Met QC Criteria: December 8, 2017
• Last Verified: December 1, 2017

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; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Dexamethasone; Prednisolone; Cyclophosphamide; Rituximab; Prednisone; Fludarabine; Vincristine; Mitoxantrone; Inotuzumab Ozogamicin
• Other Study ID Numbers: 3129K4-3301; B1931006 (Other Identifier: Alias Study Number); 2007-000219-27 (EudraCT Number)