The purpose of the study is to determine the tolerability, the initial safety profile and maximum tolerated dose, and to obtain preliminary information on the antitumor activity of inotuzumab ozogamicin \[CMC-544\] in combination with rituximab in subjects with follicular, diffuse large B-Cell, or mantle cell NHL.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
119
IV, 1.8 mg/m2, q4w
IV, 1.8 mg/m2, q4w
IV, 1.8 mg/m2, q4w
Maximum Tolerated Dose (MTD) of Inotuzumab Ozogamicin in Combination With Rituximab (375 mg/m^2 )
Inotuzumab ozogamicin was dose escalated (3 to 6 evaluable participants enrolled per dose cohort) during the first 28 days after the first administration of inotuzumab ozogamicin + rituximab. Enrollment at the next dose level or enrollment of additional subjects into a cohort proceeded according to the following criteria: 0 dose-limiting toxicity (DLT) by Day 28 of first dose move to higher dose, 1 participant reporting DLT but no others in cohort by Day 28 of first dose move to higher dose, greater than 2 participants reporting DLT by Day 28 of first dose stop and prior dose level considered MTD. The worldwide medical monitor and investigators reviewed all significant study drug-related toxicities to determine if the dose escalation rules were satisfied and whether the dose escalation schedule required modification.
Time frame: First 28-day cycle
Percentage of Participants With a Treatment Emergent Adverse Event (TEAE) (Safety Population)
A TEAE is any event that occurred after the first dose of study drug up to 56 days post the last dose of study drug (either rituximab or inotuzumab ozogamicin).
Time frame: Protocol reporting period of from informed consent to at least 28 days after the last dose. This outcome measure time frame: From the first dose of study drug to up to 56 days after the last dose of either study drug.
Percentage of Participants With Complete Response (CR), Unconfirmed CR (CRu), or Partial Response (PR)
CR: a. Complete disappearance of all detectable clinical and radiographic evidence of disease, disease-related symptoms, and normalization of NHL assignable biochemical abnormalities ; b. lymph nodes and nodal masses must have regressed to normal size; c. Spleen regressed in size and not palpable on physical exam, size of other organs enlarged due to disease decreased in size; d. Repeat bone marrow infiltrate clear. CRu: CR but allows for a. Residual lymph node mass \>1.5 cm in greatest transverse diameter has regressed by more than 75% in diameter. Individual nodes that were previously confluent regressed more than 75 % in their product diameters; b. Indeterminate bone marrow. PR: a. ≥50 % decrease in product of the diameters (SPD) of the 6 largest dominant nodes or nodal masses; b. No increase in size of other nodes, liver, or spleen, c. Liver or spleen nodules regressed ≥50% in the SPD; d. Other organs usually assessable, no measurable disease present.
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rituximab 375 mg/m\^2 via IV infusion on Day 1
University of Alabama at Birmingham-
Birmingham, Alabama, United States
IDS Pharmacy
Birmingham, Alabama, United States
University of Alabama at Birmingham-
Birmingham, Alabama, United States
California Cancer Care, Inc.
Greenbrae, California, United States
University of California Medical Center
San Francisco, California, United States
California Cancer Care
San Mateo, California, United States
Emory Clinic
Atlanta, Georgia, United States
Emory University Hospital
Atlanta, Georgia, United States
Emory University Investigational Drug Service
Atlanta, Georgia, United States
Northwestern Medical Faculty Foundation
Chicago, Illinois, United States
...and 28 more locations
Time frame: Approximately every 2 (during treatment) or 3 (during follow-up) to 6 months for up to 5 years from 1st dose
Kaplan-Meier Estimates of Progression Free Survival (PFS)
The Kaplan-Meier method was used to determine PFS. 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression. Relapsed or Progressive Disease (PD) requires the following: a. Appearance of any new lesions, b. Increase by \>= 50% in the size of previously involved sites, c. \>= 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node, d. \>= 50% increase from nadir in the product diameter of any previously identified abnormal node for PRs or nonresponders, e. Enlarging spleen or liver.
Time frame: From the date of first dose of test article until the first date on which disease progression or death was documented or new anticancer start, any of which could be reported up to 5 years post last dose
Kaplan-Meier Estimates of the Probability of Being Progression Free at 6 Months
Progression Free Survival is defined as the time interval from the first dose of test article until the first date on which relapsed disease, progression, initiation of new anti-cancer treatment due to persistent/refractory disease, or death was documented, censored at the last tumor evaluation.
Time frame: From the first dose to 6 months after first dose
Kaplan-Meier Estimates of Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause, censoring at the date of last contact. The Kaplan-Meier method was used to determine OS. 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time frame: From the first dose up to 5 years post last dose
Kaplan-Meier Estimates of the Probability of Survival at 6 Months
Overall Survival (OS) was defined as the time from randomization to death due to any cause, censoring at the date of last contact. The Kaplan-Meier method was used to determine OS. 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time frame: From the first dose to 6 months after first dose.
Kaplan-Meier Estimates of Time to Tumor Progression (TTP)
TTP is defined as the interval from the first dose of the test article until the first date on which relapsed disease or progression, or death secondary to progression is documented, censored at the last disease assessment. Relapsed or Progressive Disease (PD) requires the following: a. Appearance of any new lesions, b. Increase by \>= 50% in the size of previously involved sites, c. \>= 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node, d. \>= 50% increase from nadir in the product diameter of any previously identified abnormal node for PRs or nonresponders, e. Enlarging spleen or liver. The Kaplan-Meier method was used to determine TTP. 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time frame: From the date of first dose of test article until the first date on which disease progression or death was documented, any of which could be reported up to 5 years post last dose.
Kaplan-Meier Estimates of the Probability of Being Event Free at 6 Months
Time-to-Tumor Progression (TTP): is defined as the interval from the first dose of the test article until the first date on which relapsed disease or progression, or death secondary to progression is documented, censored at the last disease assessment. Relapsed or Progressive Disease (PD) requires the following: a. Appearance of any new lesions, b. Increase by \>=50% in the size of previously involved sites, c. \>= 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node, d. \>= 50% increase from nadir in the product diameter of any previously identified abnormal node for PRs or nonresponders, e. Enlarging spleen or liver. The Kaplan-Meier method was used to determineTTP. 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time frame: From enrollment to up to 6 months from 1st dose.
Duration of Response (CR+CRu+PR)
Time from date measurement criteria met for CR, CRu, or PR (whichever occurred first) until first date relapsed disease/date of death. CR: Complete disappearance of all detectable clinical, radiographic evidence of disease, disease-related symptoms, normalization of NHL assignable biochemical abnormalities; lymph nodes, nodal masses regressed to normal size; spleen size regressed, not palpable on physical exam, size of other organs enlarged due to disease. CRu: CR but allows for: residual lymph node mass \>1.5 cm in greatest transverse diameter that regressed \>75% in product diameter. Individual nodes previously confluent, regressed by \>75% in their product diameters; Indeterminate bone marrow. PR: ≥50% decrease in SPD of 6 largest dominant nodes/nodal masses; No increase in size of other nodes, liver, or spleen; Splenic/hepatic nodules regressed by ≥50% in SPD; Except splenic/hepatic nodules, involvement of other organs assessable and no measurable disease present.
Time frame: Time from date measurement criteria are met for CR, CRu, or PR (whichever status is recorded first) until the first date relapsed disease or date of death (whichever occurs first) is objectively documented.
Area Under the Serum Concentration-time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Inotuzumab Ozogamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Serum concentration of inotuzumab ozogamicin on Dosing Days 30 and 58 were measured. AUCinf of inotuzumab ozogamicin was reported. AUCinf: AUClast (area under the serum concentration-time profile for inotuzumab ozogamicin from time zero to the time of the last quantifiable concentration) +(Clast \[last quantifiable concentration\]/kel \[elimination rate constant\]) where Clast is the predicted serum concentration of inotuzumab ozogamicin at the last quantifiable timepoint estimated from the log-linear regression analysis. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
AUClast of Inotuzumab Ozogamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Serum concentration of inotuzumab ozogamicin on Dosing Days 1, 30 and 58 were measured. AUC of inotuzumab ozogamicin was reported. AUClast is area under the serum concentration-time profile from time zero to the time of the Clast, using Linear/Log trapezoidal method. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time of the Last Quantifiable Serum Concentration in a Dosing Interval (Tlast) of Inotuzumab Ozogamicin in Participants Receving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Tlast of inotuzumab ozogamicin on Dosing Days 1, 30, and 58 was reported. Tlast: Time of last quantifiable concentration of inotuzumab ozogamicin. Observed directly from data. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Area Under the Steady-state Serum Concentration-time Curve (AUCtau) of Inotuzumab Ozogamicin in Participants Receving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Steady-state serum concentrations of inotuzumab ozogamicin on Dosing Days 1, 30 and 58 were measured. AUCtau of inotuzumab ozogamicin was reported. AUCtau=AUC over dosage interval tau calculated using Linear/log trapezoidal method. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Peak Serum Concentration (Cmax) of Inotuzumab Ozogamicin in Participants Receving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Serum concentration of inotuzumab ozogamicin on Dosing Days 1, 30, and 58 were measured. Cmax of inotuzumab ozogamicin was reported. Cmax was observed directly from data. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time to Reach Maximum Concentration (Tmax) of Inotuzumab Ozogamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Tmax: Time at which Cmax occurs. Observed directly from data as time of first occurrence. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Average Serum Concentration at Steady State (Cav) of Inotuzumab Ozogamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Cav: AUCtau (Area under the concentration time profile)/tau for Dosing Day 30 Cycle 2 and Dosing Day 58 Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Minimum Observed Serum Trough Concentration (Cmin) of Inotuzumab Ozogamicin in Participants Receiving Inotuzumab+Rituximab on Dosing Day 30 and Day 58
Cmin: Lowest concentration observed during the dosing interval tau. Observed directly from data from Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Clearance (CL) of Serum Inotuzumab Ozogamicin in Participants Receiving Inotuzumab+Rituximab on Dosing Day 30 and Day 58
Clearance is defined as Dose/AUCinf. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Steady-state Volume of Distribution (Vss) of Inotuzumab Ozogamicin in Serum in Participants Receiving Inotuzumab MTD+Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Vss of inotuzumab ozogamicin on Dosing Days 30 and 58 were reported. Vss=CL\*MRT (mean residence time). Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
MRT of Inotuzumab Ozogamicin in Serum in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
MRT: AUMCinf/AUCinf - DOF (degrees of freedom)/2, where AUMCinf is the area under the first moment curve derived using the linear/log trapezoidal method, and DOF is the duration of the IV infusion dose. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Serum Decay Half-Life (t1/2) of Inotuzumab Ozogamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Termnial half-life (t½): Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
AUCinf of Total Calicheamicin (Conjugated + Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
AUCinf: AUClast+(Clast/kel) where Clast is the predicted serum concentration at the last quantifiable timepoint estimated from the log-linear regression analysis. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
AUClast of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
AUClast: AUC over dosage interval through last measurable time point, Tlast, using Linear/Log trapezoidal method. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time of the Last Quantifiable Concentration in a Dosing Interval (Tlast) of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Tlast: Time of last quantifiable concentration. Observed directly from data. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Area Under the Steady-state Serum Concentration-time Curve (AUCtau) for Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30, and Day 58
AUCtau=AUC over dosage interval tau calculated using Linear/log trapezoidal method. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Peak Serum Concentration (Cmax) of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Cmax: Observed directly from data Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time of Observed Maximum Concentration (Tmax) of Total Calicheamicin (Conjugated+Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Tmax: Time at which Cmax occurs. Observed directly from data as time of first occurrence. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Average Serum Concentration (Cav) of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Cav: AUCtau/tau for Dosing Day 30 Cycle 2 and Dosing Day 58 Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Minimum Observed Serum Trough Concentration (Cmin) of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Cmin: Lowest concentration observed during the dosing interval tau. Observed directly from data from Day 30 for Cycle 2; and Day 58 for Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Clearance (CL) of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Clearance defined as Dose/AUCinf. Corresponds to Dosing Day 30 for Cycle 2 and dosing Day 58 for Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Steady-state Volume (Vss) of Total Calicheamicin (Conjugated Plus Unconjugated) Distribution in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Vss: Steady-state volume of distribution CL\*MRT of inotuzumab ozogamicin Day 30 for Cycle 2; and Day 58 for Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Mean Residence Time (MRT) of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
MRT: AUMCinf/AUCinf - DOF/2, where AUMCinf is the area under the first moment curve derived using the linear/log trapezoidal method, and DOF is the duration of the IV infusion dose. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Serum Decay Half-Life (t1/2) of Total Calicheamicin (Conjugated Plus Unconjugated) in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Termnial half-life (t½): Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Area Under the Steady-state Serum Concentration-time Curve (AUClast) of Unconjugated Calicheamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
AUClast: AUC over dosage interval through last measurable time point, Tlast, using Linear/Log trapezoidal method. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time of the Last Quantifiable Concentration in a Dosing Interval (Tlast) of Unconjugated Calicheamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Tlast: Time of last quantifiable concentration. Observed directly from data. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Peak Serum Concentration (Cmax) of Unconjugated Calicheamicin in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Cmax: Observed directly from data Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time of Observed Maximum Concentration (Tmax) of Unconjugated Calicheamicin in Participants Receiving Inotuzumab Ozogamicin + Rituximab on Dosing Day 1, Day 30 and Day 58
Tmax: Time at which Cmax occurs. Observed directly from data as time of first occurrence. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Minimum Observed Serum Trough Concentration (Cmin) of Unconjugated Calicheamicin in Participants Receiving Inotuzumab Ozogamicin+Rituximab on Dosing Day 30 and Day 58
Cmin: Lowest concentration observed during the dosing interval tau. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Area Under the Serum Concentration-time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m2 on Dosing Day 30 and Day 58
AUCinf: AUClast+(Clast/kel) where Clast is the predicted serum concentration at the last quantifiable timepoint estimated from the log-linear regression analysis. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Area Under the Steady-state Concentration-time Curve (AUClast) of Serum Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
AUClast: AUC over dosage interval through last measurable time point, Tlast, using Linear/Log trapezoidal method. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time of the Last Quantifiable Concentration in a Dosing Interval (Tlast) of Serum Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Tlast: Time of last quantifiable concentration. Observed directly from data. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Serum Decay Half-Life (t1/2) of Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab on Dosing Day 30 and Day 58
Termnial half-life (t½): Loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Area Under the Steady-state Serum Concentration-time Curve (AUCtau) of Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD+ Rituximab 375 mg/m^2 on Dosing Day 1, Day 30, and Day 58
AUCtau=AUC over dosage interval tau calculated using Linear/log trapezoidal method. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Peak Concentration (Cmax) of Serum Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Cmax: Observed directly from data Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Time to Reach Maximum Concentration (Tmax) of Serum Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 1, Day 30 and Day 58
Tmax: Time at which Cmax occurs. Observed directly from data as time of first occurrence. Study Days Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 1 for Cycle 1; Dosing Day 30 for Cycle 2; and Dosing Day 58 for Cycle 3.
Time frame: Cycle 1, Days 1 (0 hour), 2 (0, 1, 4 hours), 4, 8, 10, 15, and 29; Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Average Serum Concentration (Cav) of Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Cav: AUCtau/tau for Dosing Day 30 Cycle 2 and Dosing Day 58 Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Minimum Observed Serum Trough Concentration (Cmin) of Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Cmin: Lowest concentration observed during the dosing interval tau. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Clearance (CL) of Serum Inotuzumab Ozogamicin Antibody in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Clearance defined as Dose/AUCinf. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85
Steady-state Volume (Vss) of Inotuzumab Ozogamicin Antibody Distribution in Participants Receiving Inotuzumab Ozogamicin MTD + Rituximab 375 mg/m^2 on Dosing Day 30 and Day 58
Vss: Steady-state volume of distribution CL\*MRT of inotuzumab ozogamicin Day 30 for Cycle 2; and Day 58 for Cycle 3. Study Days Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57 and Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85 correspond to Dosing Day 30 for Cycle 2 and Dosing Day 58 for Cycle 3.
Time frame: Cycle 2, Days 30 (0, 1, 4 hours), 32, 36, 38, 43, 50, and 57; Cycle 3, Days 58 (0, 1, 4 hours), 60, 64, 66, 71, 78, and 85