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Diffuse Large B-cell-lymphomaPhase 1/2NCT03064867

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

A Phase 1/2 study testing Venetoclax, Rituximab and Ifosfamide in people with Diffuse Large B-cell-lymphoma, run by Molly Gallogly at 3 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Diffuse Large B-cell-lymphoma
What is being tested?
Venetoclax, Rituximab and Ifosfamide
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
65 participants
Where
3 sitesUnited States
Study dates
26 Jun 2017to 12 Aug 2023
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.
  • Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL based on Hepatitis B serological testing as follow:
  • 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
  • Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status) should have a HBV DNA testing performed and protocol eligibility determined as follow:
  • If HBV DNA is positive, the subject is ineligible.
  • If HBV DNA is negative, the subject may be included but must undergo HBV DNA PCR testing monthly x 3 months beginning from the start of treatment
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document.
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of venetoclax or 18 months after the last dose of rituximab, whichever is longer.
  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
  • With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of rituximab. Men must refrain from donating sperm during this same period.
  • With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of rituximab to avoid exposing the embryo.

Who cannot join

  • 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 .
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  • 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.
  • Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent). Brief (<15 days) treatment with glucocorticoids (prednisone 100 mg by mouth daily, or equivalent) is acceptable.
  • Known allergy to both xanthine oxidase inhibitors and rasburicase.
  • Use of warfarin is prohibited. Anticoagulation with low-molecular weight heparin (i.e. enoxaparin) or direct thrombin inhibitors is permitted.
  • The following concomitant medications are not allowed from 7 days prior to the first dose of study drug and during venetoclax administration: Strong CYP3A4 inhibitors including but not limited to fluconazole, ketoconazole, and clarithromycin or strong CYP3A4 inducers included but not limited to rifampin, carbamazepine.
  • Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment.
  • Concomitant medications that fall into the categories below could potentially lead to adverse reactions and should be considered with caution.
  • Moderate/Weak CYP3A inducers such as efavirenz and oxcarbazepine
  • CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins (because of expected inhibition of the metabolism of CYP2C8 substrates) by venetoclax
  • CYP2C9 substrates such as tolbutamide (because of expected inhibition of the metabolism of CYP2C9 substrates by venetoclax. It is recommended to exclude CYP2C9 substrates with a narrow therapeutic index such as phenytoin.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44106-5065

  • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44195

  • Washington University School of Medicine, Siteman Cancer Center

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: Phase I/II Trial of Venetoclax in Combination With R-ICE (V+RICE) Chemotherapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

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).

Read the detailed description

Primary Objective:

Establishment of safety of V+RICE in order to identify the recommended Phase II dose (RPD2)

Secondary Objectives:

  1. Determine the overall response rate (ORR) of V+RICE relative to historical controls of RICE alone in r/r DLBCL.
  2. Determine the proportion of patients who proceed to autologous stem cell transplantation after V+RICE relative to historical controls.
  3. Describe the progression-free survival (PFS) and overall survival (OS) for patients treated with V + RICE who do and do not proceed to auto-Stem Cell Transplant, relative to historical controls.
  4. Measure total number of peripheral blood stem cells collected in patients treated with V + RICE who proceed to stem cell mobilization/harvesting, compared to historical controls.
Being tested
Venetoclax, Rituximab, Ifosfamide, Carboplatin, Etoposide
Keywords
venetoclax, rituximab, ifosfamide, carboplatin, etoposide
Medical subject headings
Dendritic Cell Sarcoma, Interdigitating

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VenetoclaxDrug

    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

  • RituximabDrug

    Also called Rituxan

    Part of R-ICE treatment:

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

  • IfosfamideDrug

    Also called Ifex

    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

  • CarboplatinDrug

    Also called Paraplatin

    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

  • EtoposideDrug

    Also called VP-16, VePesid

    Part of R-ICE treatment:

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

Study groups in NCT03064867
Study groupRoleWhat they receive
V+RICEExperimentalVenetoclax 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.
Receives: Drug: Venetoclax; Drug: Rituximab; Drug: Ifosfamide; Drug: Carboplatin; Drug: Etoposide

What is being measured

The primary outcome is the main question the study is designed to answer.

  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%.

    Measured: Up to 12 weeks

Secondary outcomes (6)

  1. Overall Response Rate

    number of patients with complete response or partial response as document in a positron emission tomography/ computerized tomography (PET/CT) scan and defined by the Revised Response Criteria for Malignant Lymphoma

    Measured: Up to 12 weeks

  2. Proportion of participants Proceeding to ASCT

    the number of patients with ASCT divided by the total number of patients

    Measured: Up to 12 weeks

  3. Progression Free Survival

    Average time disease did not progress as based on the Revised Response Criteria for Malignant Lymphoma up to 12 weeks

    Measured: Up to 12 weeks

  4. Overall Survival

    Average time participants are alive from starting treatment to death or 12 weeks, whichever comes first

    Measured: Up to 12 weeks

  5. Number of Peripheral Blood Stem Cells Collected

    Estimated through measurement of CD34+ cells/kg

    Measured: Up to 12 weeks

  6. Median Number of cluster of differentiation 34 (CD34+) Cells/kg

    Median value of CD34+ in cells/kg collected from patients

    Measured: Up to 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Feb 2017
  2. Study start26 Jun 2017
  3. Primary completion12 Aug 2022
  4. Study completion12 Aug 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
65 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03064867
Sponsor's protocol ID
CASE2415
Status last verified
Nov 2022
First submitted
22 Feb 2017
Last updated
16 Nov 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Venetoclax, Rituximab and Ifosfamide in people with Diffuse Large B-cell-lymphoma, run by Molly Gallogly at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 16 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recommended Phase II Dose (time frame: Up to 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03064867.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Nov 2022.

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