Venetoclax Plus R-ICE Chemotherapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

NCT03064867 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: CASE2415
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of this study is to determine the correct dose and safety of adding a new cancer drug, venetoclax, to a standard combination of chemotherapy drugs as a second treatment for relapsed/refractory DLBCL. In this study, venetoclax will be added to RICE (rituximab, ifosfamide, carboplatin, etoposide), a common set to cancer drugs used as a second line treatment for relapsed/refractory DLBCL. Venetoclax, is a new targeted anti-cancer drug, which works by mimicking a particular protein produced by the tumor and interrupting its normal processes, ultimately causing the tumor cells to die. Adding venetoclax to the standard RICE regimen is believed to increase the chance of getting cancer into remission. Venetoclax is experimental because it is not approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory DLBCL. Venetoclax has been FDA approved for use in patients with chronic lymphocytic leukemia (CLL).

Conditions

Diffuse Large B-cell-lymphoma

Keywords

venetoclax; rituximab; ifosfamide; carboplatin; etoposide

Outcome Measures

Primary Outcomes (1)

• Recommended Phase II Dose

  A maximum of 18 patients can theoretically participate in the initial dose escalation with Retinoic and Lithium, based on 4 dose levels with a maximum of 6 patients at each dose level. At a true dose limiting toxicity rate of 20%, the chance of escalating to the next dose level is 71% and of establishing the lower dose level as maximum tolerated dose is 29%.

  Up to 12 weeks

Secondary Outcomes (6)

• Overall Response Rate

  Up to 12 weeks

• Proportion of participants Proceeding to ASCT

  Up to 12 weeks

• Progression Free Survival

  Up to 12 weeks

• Overall Survival

  Up to 12 weeks

• Number of Peripheral Blood Stem Cells Collected

  Up to 12 weeks

Other Outcomes (2)

• Analysis for Myc

  Up to 12 weeks

• Analysis for Bcl-2

  Up to 12 weeks

Study Arms (1)

V+RICE

EXPERIMENTAL

Venetoclax given in combination with R-ICE chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide) Phase I part of this study is a 3 + 3 design, with 3 dose levels, a minimum of 6 participants (maximum of 18) will be required to identify the recommended phase 2 dose (RP2D). Phase II involvs two stages: In stage I, a total of 16 participants will be accrued. If there are 7 or fewer complete responses (CR), the study will be stopped. Otherwise, an additional 30 participants will be accrued in stage II. The maximum number of treatment cycles with V+RICE is three. Participants who achieve complete remission at the interim response assessment after 2 cycles may omit cycle 3 in order to proceed to subsequent consolidation therapy with autologous stem cell transplant (AHSCT). Participants will proceeed to other treatment including RICE, other chemotherapy, peripheral blood stemm cell collection, and ASCT per institutional guidelines.

Drug: Venetoclax; Drug: Rituximab; Drug: Ifosfamide; Drug: Carboplatin; Drug: Etoposide

Interventions

Venetoclax DRUG

Beginning with 400mg daily on days 1-10 of cycle 1-3 Phase I dose escalation scheme: Dose Level -2 (DL-2): 100 mg daily, days 1-10, cycle 1-3 DL-1: 200 mg daily, days 1-10, cycle 1-3 DL1: 400 mg daily, days 1-10, cycle 1-3 DL2: 600 mg daily, days 1-10, cycle 1-3 DL3: 800 mg daily, days 1-10, cycle 1-3 Phase II: Given at a dose of 400mg daily for 5 days

V+RICE

Rituximab DRUG

Part of R-ICE treatment: Rituximab: 375 mg/m\^2 intravenously (IV) on Day 1 of R-ICE every 21 days

Also known as: Rituxan

V+RICE

Ifosfamide DRUG

Part of R-ICE treatment: Ifosfamide: 5,000 mg/m\^2 mixed together with mesna at a dose of 5,000 mg/m\^2 over 24 hours beginning on Day 2 and completing on Day 3 of each 21-day cycle

Also known as: Ifex

V+RICE

Carboplatin DRUG

Part of R-ICE treatment: Carboplatin: At a dose corresponding to an AUC = 5 based on Cockcroft-Gault calculation of GFR using adjusted body weight. Carboplatin is given IV on the Day 2 of RICE of each 21 day cycle

Also known as: Paraplatin

V+RICE

Etoposide DRUG

Part of R-ICE treatment: Etoposide: 100 mg/m2by IV daily on 3 consecutive days (Days 1-3) of each 21-day cycle

Also known as: VP-16, VePesid

V+RICE

Eligibility Criteria

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

You may qualify if:

• Histological confirmation of relapsed/refractory diffuse large B-cell lymphoma after prior rituximab and anthracycline-containing systemic treatment regimen such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride), R-HyperCVAD (rituximab, cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone) etc. A biopsy immediately before enrollment is not required.
• Subjects must have received no more than 2 prior systemic therapies for lymphoma. Prior therapy with systemic rituximab monotherapy or conventional chemotherapy (i.e. bendamustine, CVP (Cyclophosphamide, Vincristine Sulfate, Prednisone) or other) ± rituximab for indolent non-Hodgkin's lymphoma (NHL) ± maintenance/extended-use rituximab will count as 1 line of systemic therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2
• Subjects must have normal organ and marrow function as defined below:
• Hemoglobin ≥ 8.0 g/dl
• Absolute neutrophil count ≥ 1,000/mcL
• Platelet count ≥ 75,000/mcL
• Total bilirubin ≤ 1.5 X the upper limit of normal (ULN) unless a known history of impaired bilirubin conjugation such as Gilbert's, for whom the maximum will be 2.5 ULN.
• Aspartate transaminase (AST) (SGOT) ≤ 2.5 X institutional ULN
• Alanine transaminase (ALT) (SGPT) ≤ 2.5 X institutional ULN
• International normalized ratio (INR) ≤ 1.5 ×ULN
• Patients must have a calculated serum creatinine clearance \> 50 mL/min using Cockcroft-Gault calculation or based on 24-hour urine collection performed within 7 days prior to treatment.
• HBsAg negative, HBcAb negative, HBsAb negative patients are eligible.
• HBsAg negative, HBcAb negative, HBsAb positive patients are eligible.
• Patients who test positive for HBsAg are ineligible

You may not qualify if:

• Prior treatment toxicities have not resolved to ≤ Grade 2 according to NCI CTCAE Version 4.0 (except clinically insignificant toxicities such as alopecia).
• Subjects receiving any other investigational agents.
• Patients with active tumor lysis syndrome (TLS) either from laboratory or clinical changes.
• Patients with active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma.
• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to rituximab or other agents used in this study.
• Subjects with uncontrolled intercurrent illness .
• HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Venetoclax. In addition, these subjects are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in subjects receiving combination antiretroviral therapy when indicated. HIV testing prior to enrollment is not required for screening but strongly encouraged for patients with no documented prior HIV assessment.
• Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody.
• Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation
• Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody \[HBcAb\] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to undergo monthly DNA testing.
• Women who are pregnant or lactating
• Malabsorption syndrome or other condition that precludes enteral route of administration
• Chemotherapy or radiation within 3 weeks of the first scheduled study treatment.
• Less than 2-year disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal prostate specific antigen (PSA) levels). Patients who have had completed all anti-cancer treatment for another primary malignancy more than 2 years prior to screening are eligible if they are not considered to have a "currently active" malignancy based on having less than a 30% risk of relapse.
• Major surgery, other than diagnostic surgery, within 2 weeks.

Sponsors & Collaborators

• Molly Gallogly: lead

Study Sites (3)

Washington University School of Medicine, Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106-5065, United States

Location

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Dendritic Cell Sarcoma, Interdigitating

Interventions

venetoclax; Rituximab; Ifosfamide; Carboplatin; Etoposide

Condition Hierarchy (Ancestors)

Histiocytic Disorders, Malignant; Neoplasms by Histologic Type; Neoplasms; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Coordination Complexes; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Molly Gallogly, MD PhD

  University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD, Division of Hematology and Oncology

Study Record Dates

• First Submitted: February 22, 2017
• First Posted: February 27, 2017
• Study Start: June 26, 2017
• Primary Completion: August 12, 2022
• Study Completion: August 12, 2023
• Last Updated: November 16, 2022

Record last verified: 2022-11

Locations

US (3)