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Diffuse Large B-Cell Lymphoma

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Etoposide

Venetoclax

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Venetoclax will be given in conjunction with 6 cycles of DA-EPOCH-R (doxorubicin hydrochloride, etoposide, vincristine sulfate, cyclophosphamide, prednisone, rituximab). The dosing schedule and regimen for DA-EPOCH-R will follow established protocols. Venetoclax will be administered days 1-10 of each 21-day cycle, with the exception of cycle 1, during which venetoclax dose will commence on day 3 and continue through day 12, so as to clarify attribution of any observed TLS and/or infusion reactions, and minimize tumor lysis syndrome (TLS) risk.

Venetoclax will be administered orally on days 3-12 in cycle 1, and days 1-10 with all subsequent cycles except dose level -1. If dose level -1 is required, venetoclax will be administered on days 3-7 in cycle 1 and 1-5 with subsequent cycles.

Rituximab will be administered as an IV infusion at 375 mg/m2 on day 1 of each cycle of DA-EPOCH-R, immediately prior to the start of chemotherapy. Oral pre-medication 650 mg of acetaminophen and 50-100 mg diphenhydramine hydrochloride will be administered 30 to 60 minutes prior to starting each infusion of rituximab. The first rituximab infusion should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr. If this rate of escalation is well tolerated the second and subsequent infusions can begin at a rate of 100 mg/hr and increase in 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.

Etoposide will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.

Vincristine Sulfate will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.

Vincristine Sulfate

Cyclophosphamide will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.

Prednisone will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. Prednisone will be given orally.

Doxorubicin Hydrochloride will be obtained from commercial supply, and will be given for a total of 6 cycles for all patients. The drug will be given by IV route.

Doxorubicin Hydrochloride

John P. Leonard, M.D.

Jeremy S. Abramson, M.D.

Sarah Rutherford, M.D.

This is a phase I, open label, single-arm, multi-center, dose-finding study of venetoclax in combination with DA-EPOCH-R in patients with aggressive B-Cell Lymphomas.

This clinical trial is for men and women with aggressive B-Cell Lymphomas which includes:

* Diffuse large B-cell lymphoma (DLBCL),
* B-cell lymphoma unclassifiable with intermediate features between DLBCL and Burkitt Lymphoma (BL),
* High grade B-cell lymphoma (HGBCL),
* Transformed indolent NHL (TiNHL). The aggressive B-cell lymphomas enrolling on this study have been recognized to have a poor prognosis with the use of conventional chemoimmunotherapy. DA-EPOCH-R is an alternative highly effective chemoimmunotherapy platform for these lymphomas and may serve as an optimal chemotherapy backbone for the incorporation of novel agents such as venetoclax.

The Bcl-2 protein plays a significant role in the regulation of cell death in malignant cells. Overexpression of Bcl-2 family proteins is associated with chemo-resistance of a broad variety of cancers, and BCL2 abnormalities are common in aggressive B-cell Lymphomas. Venetoclax is a highly selective Bcl-2 family protein inhibitor that binds to Bcl-2 family proteins to potentially overcome resistance and enhance responses to therapy. This study has been designed to evaluate the safety and preliminary efficacy of venetoclax in combination with DA-EPOCH-R.

Subjects will receive venetoclax in conjunction with six 21-day cycles of DA-EPOCH-R. Dosing for DA-EPOCH-R will follow established protocols. Venetoclax will be administered on days 3 through 12 during cycle 1 and days 1 through 10 of each subsequent cycle. Following completion of therapy, subjects will be followed every three months for up to two years. Subjects removed from study due to toxicity will be followed until resolution or stabilization of the toxicity.

Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas

Phase I Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas

Determination of the maximal tolerated dose (MTD)

Determination of dose limiting toxicity (DLT)

Define incidence and severity of adverse events, defined according to CTCAE v 4.0.

Genentech, Inc.

Massachusetts General Hospital

M.D. Anderson Cancer Center

Weill Medical College of Cornell University

Heart and Blood Diseases

Symptoms and General Pathology

Leukemia

Leukemia, Lymphoid

Multiple Myeloma

Neoplasms, Plasma Cell

Hematologic Neoplasms

Leukemia, Lymphocytic, Chronic, B-Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

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Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

IDP-121 will be administered as a 4-hours i.v. infusion twice a week (3 weeks on, 1 week off) on days 1, 4, 8, 11, 15 and 18 in 28-day treatment (a Cycle) (Table 4). A minimum interval of 3 days and no more than 5 days between dosing is allowed.

Patients can receive IDP-121 until disease progression, unacceptable toxicity or any other discontinuation criteria are met, or for a maximum treatment period of 1 year, whichever occurs first. Patients at the RP2D may enter the expansion phase.

Additional 17 patients will be enrolled for treatment at the RP2D level to further study safety and evaluate efficacy. DP-121 will be administered as a 4-hours i.v. infusion twice a week (3 weeks on, 1 week off) on days 1, 4, 8, 11, 15 and 18 in 28-day treatment Patients can receive IDP-121 until disease progression, unacceptable toxicity or any other discontinuation criteria are met, or for a maximum treatment period of 1 year, whichever occurs first.

IDP-121 is a new chemical entity specifically designed to directly target cMyc protein that has demonstrated activity in multiple liquid and solid tumor cell lines and preclinical animal models

IDP-121

David Molina, PhD

Laura Nevola, PhD

Enrique Ocio San Miguel

María Victoria Mateos Manteca

Francesc Bosch Albareda

Joaquín Martínez López

Valentín Cabañas Perianes

Enrique Ocio San Miguel, MD, PhD

The main aims of this 2-part study are:

* Phase I: To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of IDP-121 in patients with multiple myeloma (MM), diffuse large B cell lymphoma not otherwise specified (DLBCL-NOS), high-grade B cell lymphoma with double or triple hit rearrangement (HGBL-DH/TH) and HGBL-NOS, and chronic lymphocytic leukemia (CLL).
* Phase II: To evaluate the overall response rate (ORR), duration of response (DoR), time to progression (TTP), progression-free survival (PFS), event-free survival (EFS) and Overall survival (OS), in patients with MM, DLBCL-NOS, HGBL-DH/TH, HGBL-NOS or CLL treated with IDP-121 at the recommended Phase 2 Dose (RP2D).

This study is an open-label, multicenter, Phase 1/2 study with a Dose-Escalation phase (Phase 1) and an Expansion phase (Phase 2).

Dose-Escalation (Phase 1): The dose-escalation phase will follow a classical 3+3 design but the first patient (sentinel) will be treated at dose level 1 (0.015 mg/kg) for one cycle, and, if no Dose-Limiting Toxicities (DLTs) occur, at dose level 2 (0.032 mg/kg) from cycle 2 onwards. Once the patient 1 (sentinel) is allowed to enter dose level 2, two additional patients will be enrolled to complete the cohort at dose level 2, and the dose-escalation phase will continue the 3+3 design. DLTs will be assessed based on the safety observed in cycle 1 (28 days) for all patients except for patient 1 (sentinel) where DLT will be assessed on safety observed in cycle 1 (at dose level 1) and cycle 2 (at dose level 2). For the first trial patient (sentinel) a single cycle will be completed (28 days) at dose level 0.015 mg/kg. Doses will not be escalated before all patients entered at the current dose level have been treated and observed for at least one complete cycle (28 days) at the intended dose- cohort IDP-121 dose and the number of DLTs among those patients in their first cycle has been determined. Before each escalation, Clinical Investigators will be consulted as part of a cohort review meeting to review and discuss all data (including safety, PK, PD and efficacy data) and agree on a dose-escalation, as appropriate.

During the study, the Sponsor and Investigators may request that cohorts be enlarged or that intermediate doses between 2 planned escalation steps be explored based on all data existing at that time, including emerging safety and efficacy data and determinations of PK and PD. Also, the study will allow for alternative IDP-121 doses and/or schedules to be evaluated based on emerging data e.g., once a week dosing of IDP-121 (instead of twice a week). Data from all patients at all dose levels will be used to guide further dose-escalation or/and the MTD/RP2D.

Expansion-Phase (Phase 2): Additional 17 patients will be enrolled for treatment at the RP2D level to further study safety and evaluate efficacy. Patients will receive 28-day cycles up to a maximum of 12 cycles of treatment or until any IDP-121 treatment discontinuation criteria are met (disease progression, unacceptable toxicity, etc). Patients in the Expansion- Phase may include one or more tumor types from those evaluated in dose-escalation.

A Phase 1/2 Study of IDP-121 in Patients With Relapsed/Refractory Hematologic Malignancies

A Phase 1/2 Multicenter, Open-label, Dose-escalation Study of IDP-121 in Patients With Relapsed/Refractory Hematologic Malignancies (CASSANDRA)

IDP Discovery Pharma S.L.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas	NCT03036904	Diffuse Large B... High Grade B-Ce...	Venetoclax Rituximab Etoposide Vincristine Sul... Cyclophosphamid... Prednisone Doxorubicin Hyd...	18 Years - 80 Years	Weill Medical College of Cornell University
Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas	NCT03036904	Diffuse Large B... High Grade B-Ce...	Venetoclax Rituximab Etoposide Vincristine Sul... Cyclophosphamid... Prednisone Doxorubicin Hyd...	18 Years - 80 Years	Weill Medical College of Cornell University
A Phase 1/2 Study of IDP-121 in Patients With Relapsed/Refractory Hematologic Malignancies	NCT05908409	Multiple Myelom... Diffuse Large B... Double Hit Lymp... High Grade B-Ce... Chronic Lymphoc... Triple Hit Lymp...	IDP-121	18 Years -	IDP Discovery Pharma S.L.

Spots Global Cancer Trial Database for double hit lymphoma