A Study of ABT-199 Plus Ibrutinib and Rituximab in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma

NCT03136497 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: Pro0000567154179060LYM1004ML30063
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

A Study of Venetoclax Plus Ibrutinib and Rituximab in Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL). Our hypothesis is that the combination therapy of BTK (Bruton's tyrosine kinase) Inhibitor Ibrutinib plus Venetoclax and Rituximab in relapsed or refractory DLBCL will have an increased activity with acceptable toxicity. Furthermore, this new novel therapeutic combination will be safe and well tolerated among this patient population.

Conditions

Relapsed Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  Define maximum tolerated dose and /or recommended phase II dose for the combinations of venetoclax (ABT-199, GDC-0199) plus Ibrutinib (PCI-32765) and rituximab in Relapsed or Refractory DLBCL by assessing the incidence of dose limiting toxicities (DLTs).

  29 days

Secondary Outcomes (3)

• Incidence of Treatment-emergent Adverse Events.

  36 Months

• Efficacy as Assessed by Progression Free Survival (PFS)

  36 Months

• Efficacy as Assessed by Overall Survival (OS)

  36 Months

Study Arms (2)

400mg ABT-199

EXPERIMENTAL

Cycle length will be 28 days. 400mg ABT-199 will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.

Drug: 400mg ABT-199; Drug: Ibrutinib; Drug: Rituximab

800mg ABT-199

EXPERIMENTAL

Cycle length will be 28 days. 800mg ABT-199 will be administered orally QD (Once Daily), continuously for 24 cycles. Ibrutinib will be administered orally QD, continuously for 24 cycles. Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1), Commercially available rituximab IV will be used.

Drug: Ibrutinib; Drug: Rituximab; Drug: 800mg ABT-199

Interventions

400mg ABT-199 DRUG

Oral dose daily until disease progression

Also known as: A-1195425.0, Venetoclax

400mg ABT-199

Ibrutinib DRUG

Oral dose daily until disease progression

Also known as: PIC-32765, Imbruvica

400mg ABT-199; 800mg ABT-199

Rituximab DRUG

Rituximab will be administered IV per institutional standards. weekly X 4 (Cycle 1); once on Day 1 of cycles 2-6 only, then every other cycle until Cycle 24 (total 18 doses of Rituxan from C1D1

Also known as: Rituxan

400mg ABT-199; 800mg ABT-199

800mg ABT-199 DRUG

Oral dose daily until disease progression

Also known as: A-1195425.0, Venetoclax

800mg ABT-199

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ECOG (Eastern Cooperative Oncology Group) Performance Status \</= 2.
• Histologically or cytologically confirmed diagnosis of advanced DLBCL.
• Ability and willingness to comply with the requirements of the study protocol
• Prior therapy: relapsed or refractory patients who have received one prior therapy are eligible. If treated with small molecule, washout therapy with a period of greater than 5 times the half-life of the molecule. Patients who have previously received high-dose chemotherapy with peripheral stem cell support are eligible. Washout period of 21 days.
• Presence of at least one lymph node evaluable or mass measurable for response.
• Age greater than or equal to 18 years.
• Recovery from any previous treatment therapy.
• Laboratory parameters:
• Absolute neutrophil count (ANC) 1000/mm3 independent of growth factor support (unless the treating physician deems the neutropenia is related to bone marrow involvement, then an ANC of \> 750/mm3 is allowed)
• Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent of transfusion support in either situation
• Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
• Aspartate Aminotransferase (AST, SGOT) and Alanine Aminotransferase (ALT, SGPT) ≤ 3 x upper limit of normal (ULN)
• Creatinine: Creatinine Clearance (CrCl) 50 ml/min (calculated using Cockcroft-Gault Formula-Appendix 2) -Prothrombin time (PT)or international normalized ratio and partial thromboplastin time (PTT) not to exceed 1.2 times the institution's normal range
• Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 3 months after Venetoclax and 12 months after Rituximab For males, these restrictions apply for 3 months after the last dose of study drug.
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.

You may not qualify if:

• Known central nervous system lymphoma.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).
• Received the following agents within 7 days prior to the first dose of venetoclax or requires chronic treatment with strong Cytochrome P450 3A4 (CYP3A) inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, itraconazole, voriconazole), moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, fluconazole, verapamil), strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine). (See Appendix 4)
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
• Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
• Use of any other standard chemotherapy, radiation therapy, or experimental drug therapy for the treatment of DLBCL within 21 days of starting treatment
• Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection or human T-cell leukemia virus 1 (HTLV-1) seropositive status
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, venetoclax or rituximab or put the study outcomes at undue risk.
• History of uncontrolled or symptomatic angina
• Ejection fraction below the institutional normal limit
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible. Patients with a malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for 2 years prior to enrollment.
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal)
• Major surgery (within 4 weeks prior to the start of the first dose of study treatment), other than for diagnosis

Sponsors & Collaborators

• Hackensack Meridian Health: lead
• Janssen Scientific Affairs, LLC: collaborator
• Genentech, Inc.: collaborator

Study Sites (1)

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

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MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

venetoclax; ibrutinib; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Joshua Zenreich
• Organization: Hackensack Meridian Health

joshua.zenreich@hmhn.org

551-996-4248

Study Officials

• Andre Goy, MD

  Hackensack Meridian Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 20, 2017
• First Posted: May 2, 2017
• Study Start: September 5, 2017
• Primary Completion: November 9, 2020
• Study Completion: November 9, 2020
• Last Updated: September 23, 2024
• Results First Posted: September 23, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)