Study Evaluating Chemotherapy in Combination With Inotuzumab Ozogamicin In Subjects With Non-Hodgkin's Lymphoma

Lymphoma, B-Cell Clinical Trial

Official title:

AN OPEN-LABEL, PHASE 1 STUDY OF R-CVP OR R-GDP IN COMBINATION WITH INOTUZUMAB OZOGAMICIN IN SUBJECTS WITH CD22-POSTIVE NON-HODGKIN'S LYMPHOMA

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01055496
• Other study ID #: 3129K2-1105
• Secondary ID: B19310032009-015
• Status: Completed
• Phase: Phase 1
• Start date: March 2010
• Est. completion date: March 2014

Study information

• Verified date: June 2019
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 103
• Est. completion date: March 2014
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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).

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin

Intervention

Drug:
• inotuzumab ozogamicin+rituximab +cyclophosphamide+vincristine+prednisone
Day 1: Rituximab at 375 mg/m2 Cyclophosphamide at 375 mg/m2 (cohort 1), 550mg/m2 (cohort 2), 750 mg/m2 (cohort 3, 4) Vincristine at 1.4 mg/m2 (max 2 mg) Day 2 Inotuzumab ozogamicin at 0.8 mg/m2 (cohort 1, 2, 3), 1.3 mg/m2 (cohort 4) Days 1-5: Prednisone at 40 mg/m2 Each cycle is 3 weeks, with a maximum of 6 cycles total.
• inotuzumab ozogamicin+rituximab+gemcitabine+cisplatinum+dexamethasone
Day 1: Rituximab at 375 mg/m2 Gemcitabine at 500 mg/m2 (cohort 1, 2b, 3b), 1000mg/m2 (cohort 2a, 3a, 4, 5) Cisplatin at 37.5 mg/m2 (cohort 1, 2a), 50mg/m2 (cohort 2b, 3a), 75mg/m2 (cohort 3b, 4, 5) Day 2: Inotuzumab ozogamicin at 0.8 mg/m2 (cohort 1, 2a, 2b, 3a, 3b, 4), 1.3mg/m2 (cohort 5) Days 1-4: Dexamethasone at 40 mg Each cycle is 3 weeks, with a maximum of 6 cycles total.

Locations

Country	Name	City	State
Belgium	UZ Gent	Gent
Belgium	UZ Gasthuisberg	Leuven
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Queen Elizabeth Health Sciences Centre	Halifax	Nova Scotia
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
France	Hopital Saint-Louis -Universite Paris VII	Paris
France	Hospital Saint-Louis - Service d'Hemato-Oncologie	Paris Cedex 10
France	Centre Hospitalier Lyon Sud - Service d'Hematologie	Pierre Benite
Hong Kong	Prince of Wales Hospital	Hong Kong
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	Cancer Institute Hospital, Japanese Foundation For Cancer Research	Koto-Ku	Tokyo
Japan	Nagoya Daini Red Cross Hospital	Nagoya	Aichi
Korea, Republic of	Samsung Medical Center	Seoul
Singapore	Singapore General Hospital	Singapore
United Kingdom	Nuffield Hospital	Eastleigh	Hants
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London
United Kingdom	Cancer Sciences Division, Somers Cancer Research Building	Southampton	Hants
United Kingdom	Spire Southampton Hospital	Southampton	Hants
United States	Northwest Medical Specialties, PLLC	Federal Way	Washington
United States	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	Northwest Medical Specialties, PLLC	Gig Harbor	Washington
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Northwest Medical Specialties, PLLC	Lakewood	Washington
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Rainier Physicians, PC	Puyallup	Washington
United States	Northwest Medical Specialties PLLC	Tacoma	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	UCB Pharma

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Hong Kong,  Japan,  Korea, Republic of,  Singapore,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Participants Reporting Dose Limiting Toxicity (DLT) Adverse Events (AEs) for Participants in the DE Cohort and the MTD Confirmation Cohort for Arm 1	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.	From the first dose of study medication (Study Day 1) to the completion of the first 21-day cycle.
Primary	Participants Reporting DLT AEs for Participants in the DE Cohort and the MTD Confirmation Cohort for Arm 2	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.	From the first dose of study medication (Study Day 1) to the completion of the first 21-day cycle.
Primary	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	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.	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.
Primary	Percentage of Participants With a Treatment Emergent AE	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).	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.
Primary	Percentage of Participants With Any Grade 3/4 Chemistry Abnormality During Therapy	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."	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.
Primary	Percentage of Participants With Any Grade 3/4 Hematology Abnormality During Therapy	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."	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.
Secondary	Percentage of Participants With a Best OR of CR or PR According to International Response Criteria for NHLs in the DE Cohorts	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.	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.
Secondary	Kaplan-Meier Estimate of the Progression-Free Survival (PFS) in the DE Cohorts	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.	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
Secondary	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	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.	6, 12 and 24 months
Secondary	Kaplan-Meier Estimate of the PFS in the MTD Confirmation/EE Cohorts	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.	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
Secondary	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.	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.	6, 12, and 24 months
Secondary	Kaplan-Meier Estimate of the Overall Survival (OS) in the DE Cohorts	OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.	From first dose of study medication through 2 year follow-up period
Secondary	Kaplan-Meier Estimates of the Probability of Being Alive at 6, 12, and 24 Months in the DE Cohorts	OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.	6, 12, and 24 months
Secondary	Kaplan-Meier Estimate of the OS in the MTD Confirmation/EE Cohorts	OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.	From first dose of study medication through 2 year follow-up period
Secondary	Kaplan-Meier Estimates of the Probability of Being Alive at 6, 12, and 24 Months in the MTD Confirmation/EE Cohorts	OS was defined from date of first dose to date of death due to any cause, censoring at the date of last contact.	6, 12, and 24 Months
Secondary	Mean Inotuzumab Ozogamicin Serum Concentrations	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.	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.

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