Study Evaluating Chemotherapy in Combination With Inotuzumab Ozogamicin In Subjects With Non-Hodgkin's Lymphoma
- Conditions
- Lymphoma, B-Cell
- Interventions
- Drug: inotuzumab ozogamicin+rituximab +cyclophosphamide+vincristine+prednisoneDrug: inotuzumab ozogamicin+rituximab+gemcitabine+cisplatinum+dexamethasone
- Registration Number
- NCT01055496
- Lead Sponsor
- Pfizer
- Brief Summary
This is a phase 1 trial designed to evaluate safety and tolerability of chemotherapy in combination with inotuzumab ozogamicin, an investigational product, in adults with CD22-positive non-Hodgkin's lymphoma. The trial will involve two arms. In one arm, subjects will receive chemotherapy regimen R-CVP (rituximab, cyclophosphamide, vincristine and prednisone). In the other arm, subjects will receive R-GDP (rituximab, gemcitabine, cisplatinum and dexamethasone). Subjects in both arms will also receive inotuzumab ozogamicin.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 103
- Dose escalation cohorts: subjects with diagnosis of CD22-positive Non-Hodgkin's Lymphoma (NHL) who have had at least 1 prior anticancer treatment, including prior treatment with rituximab and chemotherapy.
- Expanded maximum tolerated dose (MTD) confirmation and preliminary efficacy cohorts: subjects with diagnosis of CD22-positive NHL who have had at least 1 prior anticancer treatment, including prior treatment with rituximab and chemotherapy or newly diagnosed subjects who are not candidates for anthracycline-based therapy.
- At least 1 measurable disease lesion that is > 1 cm in the longest transverse diameter, with a product of the diameters > 2.25 cm2 by CT or magnetic resonance imaging (MRI).
- Candidate for potentially curative therapy such as stem cell transplantation.
- Prior allogeneic hematopoietic stem cell transplantation (HSCT).
- Prior autologous transplantation, radioimmunotherapy, or other anti CD22 immunotherapy <= 6 months before the first dose of investigational product.
- More than 3 previous combination chemotherapy (2 or more cytotoxics) anticancer regimens.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Arm 1 (R-CVP) inotuzumab ozogamicin+rituximab +cyclophosphamide+vincristine+prednisone Subjects in arm 1 will be enrolled in dose escalation cohorts that will initially evaluate an escalating dose of cyclophosphamide in combination with set doses of inotuzumab ozogamicin, vincristine, prednisone, and rituximab. Arm 2 (R-GDP) inotuzumab ozogamicin+rituximab+gemcitabine+cisplatinum+dexamethasone Subjects in arm 2 will be enrolled in dose escalation cohorts that will initially evaluate escalating doses of gemcitabine and/or cisplatinum in combination with set doses of inotuzumab ozogamicin, dexamethasone, and rituximab.
- Primary Outcome Measures
Name Time Method Participants Reporting Dose Limiting Toxicity (DLT) Adverse Events (AEs) for Participants in the DE Cohort and the MTD Confirmation Cohort for Arm 1 From the first dose of study medication (Study Day 1) to the completion of the first 21-day cycle. DLT was defined as: febrile neutropenia, Grade (Gr) 4 neutropenia ≥7 days, Gr 4 thrombocytopenia ≥7 days, Gr 3/4 thrombocytopenia associated with bleeding requiring a transfusion, Gr 3/4 non-hematologic toxicity (except alopecia) ≥7 days or treatment-related and clinically significant irrespective of duration, ≥Gr 3 QTc prolongation, Gr 4 alanine or aspartate aminotransferase, Gr 2 hyperbilirubinemia (greater than (\>)1.5 x upper normal limit) \>7 days, delayed recovery from a treatment-related toxicity that prevented re-dosing by \>7 days, or Granulocyte-colony stimulating factor treatment during the first cycle.
Participants Reporting DLT AEs for Participants in the DE Cohort and the MTD Confirmation Cohort for Arm 2 From the first dose of study medication (Study Day 1) to the completion of the first 21-day cycle. DLT was defined as: febrile neutropenia, Grade (Gr) 4 neutropenia ≥7 days, Gr 4 thrombocytopenia ≥7 days, Gr 3/4 thrombocytopenia associated with bleeding requiring a transfusion, Gr 3/4 non-hematologic toxicity (except alopecia) ≥7 days or treatment-related and clinically significant irrespective of duration, ≥Gr 3 QTc prolongation, Gr 4 alanine or aspartate aminotransferase, Gr 2 hyperbilirubinemia (greater than (\>)1.5 x upper normal limit) \>7 days, delayed recovery from a treatment-related toxicity that prevented re-dosing by \>7 days, or Granulocyte-colony stimulating factor treatment during the first cycle.
Percentage of Participants With Best Overall Response (OR) of Complete Response (CR) or Partial Response (PR) According to International Response Criteria for NHLs in the MTD and EE Cohorts From first dose of study medication through 2 year follow-up period, including but not limited to planned assessments scheduled every 9 to 24 weeks. OR was evaluated according to the International Response Criteria for NHLs. CR was defined as complete disappearance of all lesions and disease-related symptoms; all nodes must have decreased to normal (less than or equal to \[≤\]1.5 centimeters \[cm\] in their greatest transverse diameter (GTD) for nodes \>1.5 cm before therapy) or ≤1 cm (short axis) in previously involved node; enlarged spleen prior to therapy must have regressed and be non-palpable; bone marrow lymphoma: infiltrate must have been cleared on repeat bone marrow aspirate and biopsy. PR was defined as \>50% decrease in the sum of the product diameters (SPD) of up to 6 index lesions. No increase in size of other nodes, liver or spleen. Splenic and hepatic nodules must have regressed by ≥50% in the SPD or GTD (for single nodules). With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. No progression of non-target disease or new lesions.
Percentage of Participants With a Treatment Emergent AE SAEs were assessed from informed consent through and including the end of treatment visit (at least 28 calendar days after last study drug administration). Non-SAEs were recorded from time of the first dose of study drug through last participant visit. An AE was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event may not necessarily have had a causal relationship with the treatment or usage. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were defined as those occurring on or after the first study drug dose day through and including 56 days post last dose of study drug. The severity of all AEs was graded by the investigator using the National Cancer Institute Common Terminology Criteria for AE Version 3.0 (NCI CTCAE v3.0).
Percentage of Participants With Any Grade 3/4 Chemistry Abnormality During Therapy Within 3 days prior to the start of each cycle, on Day 8 of each cycle, on Day 15 of Cycles 1, 2, and 3, and the end-of-treatment visit. Each Cycle is 21 Days. The following parameters were analyzed for blood chemistry: blood urea nitrogen (or urea), creatinine, glucose, calcium, sodium, potassium, phosphorus, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, total bilirubin (and direct bilirubin, if total bilirubin was elevated), alkaline phosphatase, uric acid (or urate), albumin and total protein. Laboratory test results were graded using the NCI CTCAE v3.0 where CTCAE Grade 3 equals "severe" and CTCAE Grade 4 equals "life threatening or disabling."
Percentage of Participants With Any Grade 3/4 Hematology Abnormality During Therapy Within 3 days prior to the start of each cycle, Day 8 of each cycle, Day 15 of Cycles 1, 2, and 3, and the end-of-treatment visit. Each Cycle is 21 Days. The following parameters were analyzed for hematology: lymphocytes, basophils, eosinophils, erythrocytes, hematocrit, hemoglobin, leukocytes, monocytes, neutrophils, platelets, prothrombin international normalized ratio, prothrombin time, fibrinogen, and activated partial thromboplastin time. Laboratory test results were graded using the NCI CTCAE v3.0 where CTCAE Grade 3 equals "severe" and CTCAE Grade 4 equals "life threatening or disabling."
- Secondary Outcome Measures
Name Time Method Percentage of Participants With a Best OR of CR or PR According to International Response Criteria for NHLs in the DE Cohorts From first dose of study medication through 2 year follow-up period, including but not limited to planned assessments scheduled every 9 to 24 weeks. OR was evaluated according to the International Response Criteria for NHLs. CR was defined as complete disappearance of all lesions and disease-related symptoms; all nodes must have decreased to normal (≤1.5 cm in their GTD for nodes \>1.5 cm before therapy) or ≤1 cm (short axis) in previously involved node; enlarged spleen prior to therapy must have regressed and be non-palpable; bone marrow lymphoma: infiltrate must have been cleared on repeat bone marrow aspirate and biopsy. PR was defined as \>50% decrease in the SPD of up to 6 index lesions. No increase in size of other nodes, liver or spleen. Splenic and hepatic nodules must have regressed by ≥50% in the SPD or GTD (for single nodules). With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. No progression of non-target disease or new lesions.
Kaplan-Meier Estimate of the Progression-Free Survival (PFS) in the DE Cohorts From first dose of study medication through 2 year follow-up period, including but not limited to planned assessments scheduled every 9 to 24 weeks PFS was defined as time from date of first dose to the earlier date of progression (including symptomatic deterioration), date of death from any cause, or initiation of new anticancer therapy for the lymphoma. Participants without an event were censored at the date of the last valid tumour assessment. A valid tumour assessment visit was defined as the tumour assessment visit with overall response of CR, PR, stable disease (SD), or disease progression (PD), but not 'Not Done' or 'Unknown'. Participants without a post-baseline tumour assessment and without a PFS event were censored on the date of first dose.
Kaplan-Meier Estimates of the Probability of Being Alive and Free From PD or New Anticancer Therapy at 6, 12, and 24 Months in the DE Cohorts 6, 12 and 24 months Measure includes death from any cause, PD (including symptomatic deterioration) during and after treatment or initiation of new anticancer therapy for the lymphoma. PD was defined as symptomatic deterioration and according to the International Response Criteria for NHL: 1) appearance of any new lesion \>1.5 cm in any axis during or at EOT, even if other lesions are decreasing, 2) at least a 50% increase from nadir in the SPD of any previously involved or single involved nodes, or the size of other lesions (splenic or hepatic). Lymph nodes with a short axis diameter of \<1.0 cm must increase by ≥50% and to a size of 1.5x1.5 cm or \>1.5 cm in the long axis, 3) 50% increase in the longest diameter of any single previously identified node \>1 cm in its short axis. PD was defined as clinical PD, new non-nodal lesions or new nodal lesion ≥1.5 cm in GTD, progression of existing non-index lesions or bone marrow that was negative and now positive.
Kaplan-Meier Estimate of the PFS in the MTD Confirmation/EE Cohorts From first dose of study medication through 2 year follow-up period, including but not limited to planned assessments scheduled every 9 to 24 weeks PFS was defined as time from date of first dose to the earlier date of progression (including symptomatic deterioration), date of death from any cause, or initiation of new anticancer therapy for the lymphoma. Participants without an event were censored at the date of the last valid tumour assessment. A valid tumour assessment visit was defined as the tumour assessment visit with OR of CR, PR, SD, or PD, but not 'Not Done' or 'Unknown'. Participants without a post-baseline tumour assessment and without a PFS event were censored on the date of first dose.
Kaplan-Meier Estimates of the Probability of Being Alive and Free From PD or New Anticancer Therapy at 6, 12, and 24 Months in the MTD Confirmation/EE Cohorts. 6, 12, and 24 months Measure includes death from any cause, PD (including symptomatic deterioration) during and after treatment or initiation of new anticancer therapy for the lymphoma. PD was defined as symptomatic deterioration and according to the International Response Criteria for NHL: 1) appearance of any new lesion \>1.5 cm in any axis during or at EOT, even if other lesions are decreasing, 2) at least a 50% increase from nadir in the SPD of any previously involved or single involved nodes, or the size of other lesions (splenic or hepatic). Lymph nodes with a short axis diameter of \<1.0 cm must increase by ≥50% and to a size of 1.5x1.5 cm or \>1.5 cm in the long axis, 3) 50% increase in the longest diameter of any single previously identified node \>1 cm in its short axis. PD was defined as clinical PD, new non-nodal lesions or new nodal lesion ≥1.5 cm in GTD, progression of existing non-index lesions or bone marrow that was negative and now positive.
Kaplan-Meier Estimate of the Overall Survival (OS) in the DE Cohorts From first dose of study medication through 2 year follow-up period OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.
Kaplan-Meier Estimates of the Probability of Being Alive at 6, 12, and 24 Months in the DE Cohorts 6, 12, and 24 months OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.
Kaplan-Meier Estimate of the OS in the MTD Confirmation/EE Cohorts From first dose of study medication through 2 year follow-up period OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.
Kaplan-Meier Estimates of the Probability of Being Alive at 6, 12, and 24 Months in the MTD Confirmation/EE Cohorts 6, 12, and 24 Months OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.
Mean Inotuzumab Ozogamicin Serum Concentrations Pre-dose on Cycle 1, Day 2; Pre-dose, 1 and 3 hours post-dose on Cycle 3, Day 2; 24 hours post-dose on Cycle 3, Day 3 and 168 hours post-dose on Cycle 3, Day 8. Pharmacokinetic (PK) samples were required for participants enrolled in the confirmatory and preliminary efficacy MTD cohorts only (Parts 2 and 3). Concentrations of inotuzumab ozogamicin in serum were determined using appropriate, validated unconjugated (also known as free) bioanalytical assays.
Trial Locations
- Locations (26)
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Rainier Physicians, PC
🇺🇸Puyallup, Washington, United States
The University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Northwest Medical Specialties, PLLC
🇺🇸Lakewood, Washington, United States
Northwest Medical Specialties PLLC
🇺🇸Tacoma, Washington, United States
UZ Gasthuisberg
🇧🇪Leuven, Belgium
Hopital Saint-Louis -Universite Paris VII
🇫🇷Paris, France
Queen Elizabeth Health Sciences Centre
🇨🇦Halifax, Nova Scotia, Canada
Spire Southampton Hospital
🇬🇧Southampton, Hants, United Kingdom
Cancer Sciences Division, Somers Cancer Research Building
🇬🇧Southampton, Hants, United Kingdom
UZ Gent
🇧🇪Gent, Belgium
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Hospital Saint-Louis - Service d'Hemato-Oncologie
🇫🇷Paris Cedex 10, France
Centre Hospitalier Lyon Sud - Service d'Hematologie
🇫🇷Pierre Benite, France
Nagoya Daini Red Cross Hospital
🇯🇵Nagoya, Aichi, Japan
Cancer Institute Hospital, Japanese Foundation For Cancer Research
🇯🇵Koto-Ku, Tokyo, Japan
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Nuffield Hospital
🇬🇧Eastleigh, Hants, United Kingdom
Singapore General Hospital
🇸🇬Singapore, Singapore
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan
Davis Cancer Pavillion and Shands Medical Plaza
🇺🇸Gainesville, Florida, United States
Shands Cancer Hospital At The University Of Florida
🇺🇸Gainesville, Florida, United States
Shands Hospital at the University of Florida
🇺🇸Gainesville, Florida, United States
Guy's and St Thomas' NHS Foundation Trust
🇬🇧London, United Kingdom
Prince of Wales Hospital
🇭🇰Hong Kong, Hong Kong