Study Evaluating Inotuzumab Ozogamicin In Acute Lymphocytic Leukemia

• ClinicalTrials.gov Identifier: NCT01363297
• Recruitment Status: Completed
• First Posted: June 1, 2011
• Results First Posted: April 13, 2017
• Last Update Posted: April 13, 2017
• Sponsor: Pfizer
• Collaborator: UCB Pharma
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

The Phase 1 portion of this study will assess the safety, tolerability and efficacy at increasing dose levels of inotuzumab ozogamicin in subjects with CD22-positive relapsed or refractory adult acute lymphocytic leukemia (ALL) in order to select the recommended phase 2 dose (RP2D) and schedule. The Phase 2 portion of the study will evaluate the efficacy of inotuzumab ozogamicin as measured by hematologic remission rate (CR + CRi) in patients in second or later salvage status.

Condition or disease	Intervention/treatment	Phase
Acute Lymphocytic Leukemia	Drug: Inotuzumab Ozogamicin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 72 participants
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Phase 1/2 Study Of Inotuzumab Ozogamicin In Subjects With Relapsed Or Refractory Cd22-positive Acute Lymphocytic Leukemia
• Study Start Date: August 2011
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: January 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Inotuzumab Ozogamicin	Drug: Inotuzumab Ozogamicin; Part 1: Administered intravenously as 2 - 3 weekly doses over a 28-day cycle for a maximum of 6 cycles. Total dose per cycle 0.8 mg/m^2 to 2.0 mg/m^2. Part 2 Expansion and Part 3 Phase 2: Administered intravenously as 3 weekly doses over a 28-day cycle for a maximum of 6 cycles. Total initial dose per cycle 1.8 mg/m^2.; Other Name: CMC-544

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Reporting Dose Limiting Toxicities (DLTs) During the Phase 1 Dose-Finding Phase [ Time Frame: Cycle 1 ]
   DLT was any of the following in the first cycle & attributable to inotuzumab ozogamicin: any greater than or equal to (≥) Grade 4 non-hematologic toxicity except nausea/vomiting (if manageable with supportive care), alopecia, & toxicities secondary to neutropenia & sepsis; prolonged myelosuppression (absolute neutrophil count [ANC] less than [<] 500 per microliter [/µL] or platelet count <25,000/µL in bone marrow with <5 percent (%) blasts & no evidence of leukemia more than 45 days beyond the most recent dose of test article); any Grade 3 non-hematologic toxicity (excluding toxicities such as alopecia or those secondary to neutropenia & sepsis) not resolving to ≥ Grade 2 within 7 days of the most recent dose of test article or was clinically significant irrespective of duration; any ≥ Grade 3 elevation of alanine aminotransferase, aspartate aminotransferase or bilirubin lasting ≥7 days; any test article related toxicity resulting in permanent discontinuation of test article.
2. Percentage of Participants With Preliminary Satisfactory Response (Complete Response [CR], CR With Incomplete Count Recovery [CRi], Partial Response [PR], or Resistant Disease [RD]) Indicating Disease Stability After First Dose During Phase 1 Dose-Finding [ Time Frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years ]
   CR was the disappearance of leukemia indicated by <5% marrow blasts and absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was as for CR except with ANC <1000/µL and/or platelets <100,000/µL. PR was an improved or no worsening of acute lymphocytic leukemia indicated by no peripheral blood blasts, and/or at least a 50% decrease in the marrow blast percentage, compared to pre-treatment value, and marrow blast percentage ≥5% and less than or equal to (≤)25% and/or C2 extramedullary disease status. RD occurred if a participant survived ≥7 days following completion of initial treatment course and had persistent leukemia in the most recent peripheral blood smear or bone marrow and/or persistent disease involvement at any extramedullary site after completion of therapy.
3. Percentage of Participants With CR or CRi During Phase 2 [ Time Frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years ]
   CR was defined as a disappearance of leukemia as indicated by <5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC <1000/µL and/or platelets <100,000/µL.
4. Percentage of Participants With CR, CRi or PR During the Phase 1 Expansion Phase [ Time Frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years ]
   CR was defined as a disappearance of leukemia as indicated by <5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC <1000/µL and/or platelets <100,000/µL. PR was defined as an improved or no worsening of acute lymphocytic leukemia as indicated by no peripheral blood blasts, and either or both of the following: at least a 50% decrease in the marrow blast percentage, compared to the pre-treatment value, and marrow blast percentage ≥5% and ≤25% and/or C2 extramedullary disease status.

Secondary Outcome Measures :

1. Percentage of Participants With CR, CRi or PR in Phase 2 [ Time Frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years ]
   CR was defined as a disappearance of leukemia as indicated by <5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC <1000/µL and/or platelets <100,000/µL. PR was defined as an improved or no worsening of acute lymphocytic leukemia as indicated by no peripheral blood blasts, and either or both of the following: at least a 50% decrease in the marrow blast percentage, compared to the pre-treatment value, and marrow blast percentage ≥5% and ≤25% and/or C2 extramedullary disease status.
2. Number of Participants With Minimal Residual Disease (MRD) Negativity in Participants Achieving CR and CRi [ Time Frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years ]
   MRD negativity was defined as <0.01% mononuclear cells.
3. Percentage of Participants With CR or CRi by Cytogenetic Category [ Time Frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years ]
   CR was defined as a disappearance of leukemia as indicated by <5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC <1000/µL and/or platelets <100,000/µL.
4. Percentage of Participants Who Had a Post-Treatment Stem-Cell Transplant (SCT) [ Time Frame: Up to approximately 2 years from first dose ]
   Post-treatment SCT rate was defined as the percentage of participants who underwent SCT following treatment with inotuzumab ozogamicin.
5. Progression Free Survival (PFS) [ Time Frame: Up to approximately 2 years from first dose ]
   PFS was defined as the time from Cycle 1 Day 1 to first documentation of PFS event (earliest date of objective progression [PD], treatment discontinuation due to global deterioration of health status, subsequent induction or transplant after best response of PR or resistant disease, relapse after CR or CRi, or death due to any cause). Participants last known to be 1) alive and 2) without a PFS event, were censored at the date of the last disease assessment that verified lack of event.
6. Duration of Remission (DoR1) for Participants Who Achieved CR or CRi [ Time Frame: Up to approximately 2 years from first dose ]
   DoR1 was defined for participants who responded as the time from the date of first documentation of Complete Hematologic Response (CR or CRi) to the date of the first documentation of relapse after CR or CRi, treatment discontinuation due to global deterioration of health status) or to death due to any cause. Participants last known to be 1) alive and 2) without a DoR1 event, were censored at the date of the last disease assessment that verified lack of event.
7. Duration of Response (DoR) for Participants Who Achieved CR/CRi or PR [ Time Frame: Up to approximately 2 years from first dose ]
   DoR was defined for participants who respond as the time from the date of first documentation of Hematologic Response (CR, CRi, or PR) to the date of the first documentation of DoR event (earliest date of PD, treatment discontinuation due to global deterioration of health status, first induction therapy or transplant after PR, relapse after CR or CRi or death due to any cause). Participants last known to be 1) alive and 2) without a DoR event, were censored at the date of the last disease assessment that verified lack of event.
8. Overall Survival (OS) [ Time Frame: Up to approximately 2 years from first dose ]
   OS was defined as the time from Cycle 1 Day 1 to date of death due to any cause. If death was not documented, censoring occurred at the date at which the participant was last known to be alive.
9. Time to Remission for Participants Who Achieved CR or CRi [ Time Frame: Up to approximately 2 years from first dose ]
   Time to remission was defined as the time from the date of first dose of study drug to the date of first documentation of hematologic remission (CR or CRi) in participants achieving remission during study therapy.
10. Time to Response for Participants Who Achieved CR/CRi or PR [ Time Frame: Up to approximately 2 years from first dose ]
    Time to response was defined as the time from the date of first dose of study drug to the date of first documentation of hematologic response (CR, CRi, or PR).
11. Time to MRD Negativity for Participants Who Achieved CR or CRi [ Time Frame: Screening, Day 21 of Cycles 1 to 6 and up to 4 to 6 weeks after the last dose (up to 34 weeks) ]
    Time to MRD negativity was defined as the time from the date of first dose of study drug to the date of first documentation of MRD negativity.
12. Duration of Follow-Up [ Time Frame: From first dose up to approximately 2 years ]
    Duration of follow-up was defined as the time from the date of first dose of study drug to the date of last contact for participants known to be alive.
13. Percentage of Cluster of Differentiation-22 Positive (CD22+) Leukemic Blasts in Abnormal B Cells in Blood by Visit [ Time Frame: Pre-dose on Days 1 and 15 of Cycles 1 and 2, and Day 1 of Cycle 4 ]
    CD22+ leukemic blasts assessed in abnormal B cells from blood (data from central laboratories only).
14. Percentage of CD22+ Leukemic Blasts in Abnormal B Cells in Bone Marrow by Visit [ Time Frame: Pre-dose on Days 1 and 15 of Cycles 1 and 2, and Day 1 of Cycle 4 ]
    CD22+ leukemic blasts assessed in abnormal B cells from bone marrow (data from central laboratories only).
15. Messenger Ribonucleic Acid (mRNA) Gene Expression [ Time Frame: Predose and postdose on Days 1 and 15 of Cycle 1 ]
    Optional blood samples for pharmacogenomic parameters were collected during Cycle 1 prior to the start of the inotuzumab ozogamicin infusion (0 hours) and 1 hour post-dose (original Final Protocol and Protocol Amendments 1 and 2) or 3 hours post-dose (Protocol Amendments 3 and 4) on Day 1 and Day 15 from those participants who provided consent. Gene expression analysis of samples collected pre- and post-dosing was performed using 96-gene TaqMan® low density array cards to examine the concordance between clinical outcome and expression of genes such as those involved in DNA damage response, apoptosis, B-cell antigen expression, glutathione metabolism, drug transport and the phosphoinositide 3-kinase/mammalian target of rapamycin pathway. Expression for each gene was reported as a normalized value, 2^-change in (∆) threshold cycle (Ct), where ∆Ct is Ct^target gene minus Ct^reference genes, averaged.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects with CD22-positive ALL with either refractory disease (i.e. disease progression or no response while receiving their most recent prior anti-cancer therapy), or relapsed disease (i.e. response to their most recent prior anti-cancer therapy with subsequent relapse). Subjects enrolled in the Phase 2 portion of the study must be due to receive salvage 2 or later therapy.
• Subjects with Philadelphia chromosome-positive (Ph+) ALL must have failed standard treatment with at least one tyrosine kinase inhibitor.
• Adequate renal and hepatic function, and negative pregnancy test for women of childbearing potential.

Exclusion Criteria:

• Subjects with isolated extramedullary relapse or active central nervous system (CNS) leukemia.
• Prior allogeneic hematopoietic stem cell transplant (HSCT) or other anti-CD22 immunotherapy within 4 months, or active graft versus host disease (GvHD) at study entry.
• Evidence or history of veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS).

Contacts and Locations

Locations

United States, California

City of Hope National Medical Center

Duarte, California, United States, 91010-3000

Stanford Unversity Cancer Clinical Trials Office

Palo Alto, California, United States, 94304

Stanford Unversity Hospital and Clinics, CTRU

Palo Alto, California, United States, 94304

Stanford Cancer Institute

Stanford, California, United States, 94305

Stanford University Hospital and Clinics

Stanford, California, United States, 94305

United States, Illinois

The University of Chicago Medical Center

Chicago, Illinois, United States, 60637

United States, Massachusetts

Massachusetts General Hospital (MGH)

Boston, Massachusetts, United States, 02114

Brigham and Women's Hospital (BWH)

Boston, Massachusetts, United States, 02115

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

Karmanos Cancer Institute at Farmington Hills

Farmington Hills, Michigan, United States, 48334

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Pfizer

UCB Pharma

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.

Stock W, Martinelli G, Stelljes M, DeAngelo DJ, Gokbuget N, Advani AS, O'Brien S, Liedtke M, Merchant AA, Cassaday RD, Wang T, Zhang H, Vandendries E, Jabbour E, Marks DI, Kantarjian HM. Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia. Cancer. 2021 Mar 15;127(6):905-913. doi: 10.1002/cncr.33321. Epub 2020 Nov 24.

DeAngelo DJ, Stock W, Stein AS, Shustov A, Liedtke M, Schiffer CA, Vandendries E, Liau K, Ananthakrishnan R, Boni J, Laird AD, Fostvedt L, Kantarjian HM, Advani AS. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Adv. 2017 Jun 27;1(15):1167-1180. doi: 10.1182/bloodadvances.2016001925. eCollection 2017 Jun 27.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01363297
• Other Study ID Numbers: B1931010; 3129K6-1106 ( Other Identifier: Alias Study Number )
• First Posted: June 1, 2011
• Results First Posted: April 13, 2017
• Last Update Posted: April 13, 2017
• Last Verified: March 2017

Keywords provided by Pfizer:

Relapsed/Refractory Acute Lymphocytic Leukemia (ALL)

Additional relevant MeSH terms:

Inotuzumab Ozogamicin; Leukemia; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Antineoplastic Agents, Immunological; Antineoplastic Agents; Antibiotics, Antineoplastic