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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Lymphoma, Follicular

Intervention / Treatment
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* Drug: inotuzumab ozogamicin
* Drug: rituximab
* Drug: rituximab
* Drug: cyclophosphamide
* Drug: vincristine
* Drug: prednisone/prednisolone
* Drug: mitoxantrone
* Drug: fludarabine
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>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<br>* IV administration, 1.8mg/m² on day 2 of each cycle every 28 days, for up to 8 cycles.<br>Drug: rituximab<br>* IV administration, 375 mg/m² on day 1 of each cycle every 28 days, for up to 8 cycles.<br>|
| Active Comparator: B<br>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<br>* intravenous rituximab at a dose of 375 mg/m2 on day 1<br>Drug: cyclophosphamide<br>* intravenous cyclophosphamide at a dose of 750 mg/m2 on day 1<br>Drug: vincristine<br>* intravenous vincristine at a dose of 1.4 mg/m2 (not to exceed 2 mg) on day 1<br>Drug: prednisone/prednisolone<br>* oral prednisone/prednisolone at a dose of 40 mg/m2 on days 1 through 5<br>Drug: mitoxantrone<br>* mitoxantrone 10 mg/m2 intravenous on day 2<br>Drug: fludarabine<br>* fludarabine 25 mg/m2 intravenous on days 2 through 4<br>Drug: dexamethasone<br>* oral dexamethasone 20 mg/day on days 1-5<br>|

What is the study measuring?
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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 |