A Phase 1 Study of Venetoclax in Combination With Inotuzumab Ozogamicin for B-cell Acute Lymphoblastic Leukemia (B-ALL)
Overview
- Phase
- Phase 1
- Intervention
- Venetoclax
- Conditions
- B-cell Acute Lymphoblastic Leukemia
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 23
- Locations
- 2
- Primary Endpoint
- Maximum tolerated dose of venetoclax in combination with inotuzumab ozogamicin
- Status
- Active, not recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
This research study is evaluating the safety and efficacy of administering venetoclax and inotuzumab ozogamicin in combination in patients with acute lymphoblastic leukemia (ALL)
The names of the study drugs involved in this study are:
- Venetoclax
- Inotuzumab ozogamicin
- Dexamethasone
Detailed Description
This is a phase I study of venetoclax in combination with inotuzumab ozogamicin for the treatment of CD22-positive (CD22+) B-cell acute lymphoblastic leukemia (B-ALL) and lymphoma (B-LBL), hereafter referred to as "ALL," in patients with disease relapsed from or refractory (R/R) to prior intensive chemotherapy. The U.S. Food and Drug Administration (FDA) has not approved venetoclax for ALL but it has been approved for other uses. Venetoclax is an oral (pill) chemotherapy that works by blocking the action of certain proteins in cancer cells that help those cells survive. The U.S. Food and Drug Administration (FDA) has approved inotuzumab ozogamicin as a treatment option for ALL but not in combination with other drugs. Inotuzumab ozogamicin is an antibody-drug conjugate. An antibody-drug conjugate is a medication where a cancer drug (chemotherapy) is attached to an antibody, an immune system protein, that targets a specific protein on the cancer cell. Inotuzumab ozogamicin is combination of an antibody that targets the CD22 protein on ALL cells and calicheamicin, a chemotherapy compound that kills cancer cells. Once the antibody portion of inotuzumab ozogamicin binds to CD22 protein on cancer cells, the calicheamicin is released into the cell, where it damages the cancer cell's DNA and causes its death. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Participants will receive study treatment for approximately 6-9 months depending on their response to the study treatment and followed for two years after completion of study. It is expected that 20 to 32 people will take part in this research study. Abbvie is supporting this research study by providing the study drug venetoclax and funding research tests and procedures.
Investigators
Marlise Luskin, MD
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Participants must have histologically confirmed CD22+ B-ALL or B-LBL.
- •Note: CD22 must be detected on ≥ 20% of lymphoblasts by flow cytometry of peripheral blood, flow cytometry of bone marrow aspirate or tissue biopsy, or immunohistochemistry of the bone marrow or tissue biopsy.
- •Note: for R/R disease: ≥ 5% lymphoblasts must be documented in the diagnostic sample (blood, marrow, or tissue biopsy).
- •Note: Participants with B-LBL (confirmed CD22-positive extramedullary disease, but none or minimal marrow involvement) are eligible if eligibility criteria otherwise met.
- •Note: Participants with Philadelphia-chromosome positive B-ALL are eligible but must be refractory to 2 or more tyrosine kinase inhibitors (TKIs), refractory to ponatinib, or ineligible to receive all available TKIs.
- •Note: Participants with chronic myeloid leukemia (CML) in lymphoid blast crisis are eligible but must be refractory to 2 or more TKIs, refractory to ponatinib, or ineligible to receive all available TKIs.
- •Participants must have disease that is relapsed or refractory (R/R) to 1 or more cycles of cytotoxic chemotherapy.
- •Note: There is no limit to number or type of prior therapies (prior inotuzumab ozogamicin is not permitted).
- •Note: Philadelphia-chromosome positive B-ALL patients previously treated with TKI are eligible without receiving cytotoxic chemotherapy if they are unsuitable for standard cytotoxic chemotherapy.
- •Participants be aged ≥ 18 years.
Exclusion Criteria
- •Absolute blast count of ≥25 K/µL prior to initiation of study treatment. Steroids, hydroxyurea, and/or vincristine may be used to reduce blast count.
- •Prior treatment with inotuzumab ozogamicin at any time.
- •Prior treatment with venetoclax for relapsed disease; if venetoclax used during first-line therapy, 60 or more days must have elapsed since last dose of venetoclax. Note: The number of patients with prior receipt of venetoclax will be capped at 50% of the participants enrolled in the dose expansion phase.
- •Treatment for ALL with chemotherapy within 14 days of first dose of study drugs except for hydroxyurea, steroids, vincristine, and/or intra-thecal chemotherapy.
- •Symptomatic central nervous systemic (CNS) disease and CNS-3 disease. Asymptomatic CNS-2 disease is permitted. Prior CNS disease is not an exclusion. See Appendix B for definition of CNS disease.
- •Participants with history of decompensated hepatic cirrhosis, veno-occlusive disease (VOD)/sinusoidal obstructive syndrome (SOS), or severe liver disease.
- •Patient with uncontrolled intercurrent illness, or severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study.
- •Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) except for alopecia.
- •Participants who are receiving any other investigational agents.
- •Participants receiving any medications or substances within 7 days that are strong CYP3A4 inhibitors (such as fluconazole, voriconazole, posaconazole, isavuconazole, and clarithromycin) or inducers (such as rifampin, rifabutin, phenytoin, carbamazepine, and St. John's Wort) of CY3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference (Appendix C). Of note, anti-fungal azole therapy may be re-introduced after venetoclax dose escalation as outlined in the protocol.
Arms & Interventions
Venetoclax + Inotuzumab Ozogamicin with Dexamethasone
Phased 28 day treatment cycles with lead in: Lead In Cycle: Dose escalated venetoclax 1x daily for days 1-3 with and Dexamethasone daily for days 1-3 lead in, 7 days total. Induction Cycle 1: Dose escalated venetoclax 1x daily for days 1-21, Dexamethasone daily for days 1-4, Inotuzumab ozogamicin on days 1, 8, and 15 Induction Cycle 2: Dose escalated venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15 Consolidation Cycles: Up to 5 cycles of dose escalated Venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15
Intervention: Venetoclax
Venetoclax + Inotuzumab Ozogamicin with Dexamethasone
Phased 28 day treatment cycles with lead in: Lead In Cycle: Dose escalated venetoclax 1x daily for days 1-3 with and Dexamethasone daily for days 1-3 lead in, 7 days total. Induction Cycle 1: Dose escalated venetoclax 1x daily for days 1-21, Dexamethasone daily for days 1-4, Inotuzumab ozogamicin on days 1, 8, and 15 Induction Cycle 2: Dose escalated venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15 Consolidation Cycles: Up to 5 cycles of dose escalated Venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15
Intervention: Dexamethasone
Venetoclax + Inotuzumab Ozogamicin with Dexamethasone
Phased 28 day treatment cycles with lead in: Lead In Cycle: Dose escalated venetoclax 1x daily for days 1-3 with and Dexamethasone daily for days 1-3 lead in, 7 days total. Induction Cycle 1: Dose escalated venetoclax 1x daily for days 1-21, Dexamethasone daily for days 1-4, Inotuzumab ozogamicin on days 1, 8, and 15 Induction Cycle 2: Dose escalated venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15 Consolidation Cycles: Up to 5 cycles of dose escalated Venetoclax 1x daily for days and Inotuzumab ozogamicin on days 1, 8, and 15
Intervention: Inotuzumab Ozogamicin
Outcomes
Primary Outcomes
Maximum tolerated dose of venetoclax in combination with inotuzumab ozogamicin
Time Frame: Enrollment to end of treatment up to 9 months
Descriptive analysis of highest dose of venetoclax that did not cause a dose limiting toxicity with toxicity type based CTCAE vs 5.0 criteria.
Secondary Outcomes
- Event-free survival (EFS)(Enrollment to end of treatment up to 9 months)
- Disease-free survival (DFS)(Enrollment to end of treatment up to 9 months)
- Overall survival (OS).(Enrollment to end of treatment up to 9 months)
- Measurable residual disease (MRD)-response(Enrollment to end of treatment up to 9 months)
- Morphologic response(Enrollment to end of treatment up to 9 months)