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NCT01232556

A Study Of Inotuzumab Ozogamicin Plus Rituximab For Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma Patients Who Are Not Candidates For Intensive High-Dose Chemotherapy

Terminated Phase 3 Results posted Last updated 8 January 2019
What this trial tests

Phase 3 trial testing Inotuzumab ozogamicin in Lymphoma, Non-Hodgkin in 338 participants. Terminated before completion.

Timeline
4 April 2011
Primary endpoint
28 March 2014
28 March 2014

Quick facts

Lead sponsorPfizer
PhasePhase 3
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment338
Start date4 April 2011
Primary completion28 March 2014
Estimated completion28 March 2014
Sites177 locations across Japan, Taiwan, Ireland, Poland, Croatia, Russia, Belgium, Sweden

Drugs / interventions tested

Conditions studied

Sponsor

Pfizer — full company profile →

Who can join

18 and older, any sex, with Lymphoma, Non-Hodgkin. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Survival Primary · From randomization up to 5 years after last dose or up to final study visit, whichever occurs first.

Overall Survival (OS) 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. The Kaplan-Meier method was used to determine OS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.

GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab9.57.0 – 14.5
Rituximab+Gemcitabine or Rituximab+Bendamustine9.57.7 – 14.1
Progression-Free Survival (PFS) Secondary · From randomization up to 2 years or final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

PFS is defined as time from date of randomization to date of progressive disease (PD, including investigator's claim of clinical progression), date of death from any cause, or initiation of a new treatment for the lymphoma due to persistent/refractory disease. The Kaplan-Meier method was used to determine PFS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression. PD requires the following: 1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of treatment, even if other lesions are d

GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab3.72.9 – 5.0
Rituximab+Gemcitabine or Rituximab+Bendamustine3.52.8 – 4.9
Percentage of Participants With A Best Overall Response of CR or Partial Response (PR) Per NCI International Response Criteria for NHL Secondary · Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment). Partial Response (PR) requires the following: 1. ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. 2. No increase in the size of other nodes, liver, or spleen. 3. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. 4. With the exception of splenic and hepatic nodules, involvement of other organs is us

GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab29.522.70 – 37.08
Rituximab+Gemcitabine or Rituximab+Bendamustine29.722.94 – 37.08
Percentage of Participants With A Best Overall Response of CR, Unconfirmed CR (unCR), PR, or Unconfirmed PR (unPR) Per NCI International Response Criteria for NHL Secondary · Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment). Partial Response (PR) requires the following: 1. ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. 2. No increase in the size of other nodes, liver, or spleen. 3. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. 4. With the exception of splenic and hepatic nodules, involvement of other organs is us

GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab41.033.40 – 48.85
Rituximab+Gemcitabine or Rituximab+Bendamustine43.636.07 – 51.36
Duration of Response Secondary · Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

The duration of overall response is measured from the first date of response until the first date that the progressive disease (PD) or death is objectively documented. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.

GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab11.567.8 – NA
Rituximab+Gemcitabine or Rituximab+Bendamustine6.935.5 – 10.8
Health Status as Assessed by the European Quality of Life 5 Dimension (EQ-5D) Questionnaire Secondary · Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported

EQ-5D consists of a descriptive system and an EQ visual analogue scale. The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. The scale, the best state is marked 100 and the worst state is marked 0, is to help the participant to say how good or bad a health state is. EQ-5D index, which was reported, was derived based on US weight. The range of EQ-5D index is -0.109 to 1.00. Higher scores mean better outcomes. The average post-baseline

GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab0.790.76 – 0.82
Rituximab+Gemcitabine or Rituximab+Bendamustine0.770.74 – 0.79
Health Related Quality of Life as Assessed by the Functional Assessment of Cancer Therapy for Lymphoma (FACT-Lym) Questionnaire Secondary · Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported

FACT-Lym is a questionnaire that begins with 27 items covering four core Health-Related Quality of Life subscales: Physical Well-being (7 items), Social/Family Well-being (7), Emotional Well-being (6), and Functional Well-being (7). The FACT-Lym also includes an additional concerns subscale (15 items). It also asks participants about their concerns about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. The participants were requested to circle one number on a 0 to 4 points scale per line to indicate how true each statement has been for him/her during

GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab120.07116.74 – 123.41
Rituximab+Gemcitabine or Rituximab+Bendamustine116.96113.74 – 120.19
Percentage of Participants With a Treatment Emergent Adverse Event (TEAE) (Safety Population) Primary · Up to 20 weeks after the first dose of study drug

Includes all TEAEs: Any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration..

% participants with a TEAE
GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab98.8
Rituximab+Gemcitabine or Rituximab+Bendamustine100.0
% participants with serious TEAE
GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab37.2
Rituximab+Gemcitabine or Rituximab+Bendamustine37.7
% participants with Grade 3 or 4 TEAE
GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab79.9
Rituximab+Gemcitabine or Rituximab+Bendamustine79.6
% participants with Grade 5 TEAE
GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab14.6
Rituximab+Gemcitabine or Rituximab+Bendamustine13.8
% participants for study drug discontinuation
GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab25.0
Rituximab+Gemcitabine or Rituximab+Bendamustine18.0
% participants with dose reductions due to TEAEs
GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab27.4
Rituximab+Gemcitabine or Rituximab+Bendamustine29.3
% participants for study drug stopped temporarily
GroupValue95% CI
Inotuzumab Ozogamicin+Rituximab31.1
Rituximab+Gemcitabine or Rituximab+Bendamustine46.1

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 22 weeks after the informed consent. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Inotuzumab Ozogamicin+Rituximab
Serious: 61/164 (37%)
Deaths:
Rituximab+Gemcitabine or Rituximab+Bendamustine
Serious: 63/167 (38%)
Deaths:

Serious adverse events (120 terms)

ReactionSystemInotuzumab Ozogamicin+Ritu…Rituximab+Gemcitabine or R…
Disease progressionGeneral disorders
PneumoniaInfections and infestations
Febrile neutropeniaBlood and lymphatic system disorders
PyrexiaGeneral disorders
HypotensionVascular disorders
AstheniaGeneral disorders
DehydrationMetabolism and nutrition disorders
HypercalcaemiaMetabolism and nutrition disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
ThrombocytopeniaBlood and lymphatic system disorders
DiarrhoeaGastrointestinal disorders
Gastrointestinal haemorrhageGastrointestinal disorders
Atrial fibrillationCardiac disorders
CellulitisInfections and infestations
InfluenzaInfections and infestations
SepsisInfections and infestations
Urinary tract infectionInfections and infestations
Spinal fractureInjury, poisoning and procedural complications
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
Renal failureRenal and urinary disorders
Venoocclusive liver diseaseHepatobiliary disorders
Decreased appetiteMetabolism and nutrition disorders
AnaemiaBlood and lymphatic system disorders
Febrile bone marrow aplasiaBlood and lymphatic system disorders
Other adverse events (44 terms — click to expand)

ReactionSystemInotuzumab Ozogamicin+Ritu…Rituximab+Gemcitabine or R…
ThrombocytopeniaBlood and lymphatic system disorders
NeutropeniaBlood and lymphatic system disorders
FatigueGeneral disorders
LeukopeniaBlood and lymphatic system disorders
NauseaGastrointestinal disorders
Aspartate aminotransferase increasedInvestigations
AnaemiaBlood and lymphatic system disorders
LymphopeniaBlood and lymphatic system disorders
ConstipationGastrointestinal disorders
Gamma-glutamyltransferase increasedInvestigations
PyrexiaGeneral disorders
VomitingGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
Alanine aminotransferase increasedInvestigations
Blood alkaline phosphatase increasedInvestigations
CoughRespiratory, thoracic and mediastinal disorders
Back painMusculoskeletal and connective tissue disorders
Oedema peripheralGeneral disorders
Abdominal painGastrointestinal disorders
AstheniaGeneral disorders
HypokalaemiaMetabolism and nutrition disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Blood creatinine increasedInvestigations
DizzinessNervous system disorders
RashSkin and subcutaneous tissue disorders
Urinary tract infectionInfections and infestations
White blood cell count decreasedInvestigations
HyperbilirubinaemiaHepatobiliary disorders
HypophosphataemiaMetabolism and nutrition disorders
Weight decreasedInvestigations
HeadacheNervous system disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Blood bilirubin increasedInvestigations
Haemoglobin decreasedInvestigations
DysgeusiaNervous system disorders
PruritusSkin and subcutaneous tissue disorders
ArthralgiaMusculoskeletal and connective tissue disorders
ChillsGeneral disorders
NasopharyngitisInfections and infestations

Most-reported serious reactions: Disease progression, Pneumonia, Febrile neutropenia, Pyrexia, Hypotension, Asthenia, Dehydration, Hypercalcaemia.

Data from ClinicalTrials.gov NCT01232556 adverse events section.

Sponsor's own description

The purpose of this study is to evaluate the efficacy of inotuzumab ozogamicin plus rituximab in relapsed/refractory aggressive Non-Hodgkin lymphoma patients who are not candidates for intensive high-dose chemotherapy. Specifically, the goal is to demonstrate the superiority of this combination compared with an active comparator arm (investigator's choice of rituximab+bendamustine or rituximab+gemcitabine) using the primary endpoint of overall survival.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Stepping forward in antibody-drug conjugate development.
    Jin Y, Schladetsch MA, Huang X, Balunas MJ, et al · · 2022 · cited 136× · PMID 34171334 · DOI 10.1016/j.pharmthera.2021.107917
  2. New agents and regimens for diffuse large B cell lymphoma.
    Wang L, Li LR, Young KH. · · 2020 · cited 109× · PMID 33317571 · DOI 10.1186/s13045-020-01011-z
  3. Advances in targeted therapy for malignant lymphoma.
    Wang L, Qin W, Huo YJ, Li X, et al · · 2020 · cited 88× · PMID 32296035 · DOI 10.1038/s41392-020-0113-2
  4. Immunoconjugates and long circulating systems: origins, current state of the art and future directions.
    Koshkaryev A, Sawant R, Deshpande M, Torchilin V. · · 2013 · cited 82× · PMID 22964425 · DOI 10.1016/j.addr.2012.08.009
  5. Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma.
    Yu B, Liu D. · · 2019 · cited 70× · PMID 31500657 · DOI 10.1186/s13045-019-0786-6
  6. Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia.
    Wynne J, Wright D, Stock W. · · 2019 · cited 50× · PMID 30622147 · DOI 10.1182/bloodadvances.2018026211
  7. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.
    Dang NH, Ogura M, Castaigne S, Fayad LE, et al · · 2018 · cited 50× · PMID 28677896 · DOI 10.1111/bjh.14820
  8. The promising role of antibody drug conjugate in cancer therapy: Combining targeting ability with cytotoxicity effectively.
    Li WQ, Guo HF, Li LY, Zhang YF, et al · · 2021 · cited 36× · PMID 34165267 · DOI 10.1002/cam4.4052

Verify or expand the search:

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Trials testing the same drug.

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Trials by the same sponsor.

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