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Immunomodulating Agents

two or three times a week dosing of hLL1 for a total of 4 weeks

milatuzumab

William Wegener, MD, PhD

This study will test different doses of anti-CD74 antibody in patients with NHL and/or CLL.

Milatuzumab (hLL1, IMMU-115), a humanized anti-CD74 monoclonal antibody. Dose escalation will utilize 4 planned dose regimens with 4.0 or 8.0 mg/kg doses administered intravenously either twice weekly (days 1 and 4) or thrice weekly (days 1, 3 and 5) for 4 consecutive weeks. The four planned dose regimens will be labeled as dose level 1 to 4 corresponding to increasing levels of the total dose of milatuzumab.

Phase I/II Study of Different Doses and Dose Schedules of Milatuzumab (hLL1) in CLL

A Phase I/II Study of Immunotherapy With Milatuzumab (hLL1) in Patients With Chronic Lymphocytic Leukemia (CLL)

Gilead Sciences

Lymphoma, Mantle-Cell

Lymphoma, Follicular

Lymphoma, B-Cell, Marginal Zone

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

B-cell Lymphoma

Mantle Cell Lymphoma

Follicular Lymphoma

Marginal Zone Lymphoma

Antineoplastic Agents

Antibodies

Venetoclax

Obinutuzumab

Immunoglobulins

Magrolimab

Antineoplastic Agents, Immunological

Window of magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg combination for two (2) cycles (28-days each, Cycles -2 and -1), then venetoclax will be added at target dose (dose determined from Arm 1). Triplet combination treatment with magrolimab + obinutuzumab + venetoclax will be 6 cycles (28-days each, Cycles 1-6); further treatment will be response-adapted.

Magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg + venetoclax 800mg PO combination administered to 6 patients for six (6) cycles (28-days each, Cycles 1-6); further treatment with additional cycles will be response-adapted. Note: DLT assessment of the magrolimab + obinutuzumab + venetoclax triplet will take place during Cycle 1. If =2 patients experience DLT, an additional 6 patients will be enrolled at DL(-1) of venetoclax 600mg with magrolimab and obinutuzumab.

Magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg + venetoclax ramp-up to target dose of 400mg over 5 weeks (35 days, Cycle 1) administered to 6 patients. Triplet combination of magrolimab + obinutuzumab + venetoclax (target dose, no ramp-up) will continue for five (5) additional cycles (28-days each, Cycles 2-6); further treatment with additional cycles will be response-adapted. Note: DLT assessment of the magrolimab + obinutuzumab + venetoclax triplet will take place during Cycle 1. If =2 patients experience DLT, an additional 6 patients will be enrolled at DL(-1) of venetoclax 200mg with magrolimab and obinutuzumab.

Window of magrolimab IV with a 1 mg/kg priming dose followed by 30mg/kg loading and maintenance doses + obinutuzumab IV 1000mg combination for two (2) cycles (28-day cycles, Cycles -2 and -1), then venetoclax safety ramp-up to target dose (dose determined from Arm 2) over 5 weeks (35-days, Cycle 1). Triplet combination treatment with magrolimab + obinutuzumab + venetoclax (target dose, no ramp-up) will continue for 5 additional cycles (28-days each, Cycles 2-6); further treatment will be response-adapted.

Administered intravenously, on Days 1, 2, 8 and 15 of Cycle 1 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg for dose finding phase. For expansion phase, administered on Days 1, 2, 8 and 15 of Cycle 2 at doses escalating from 100mg - 1000mg then on the first day for all subsequent cycles at 1000mg.

For FL patients in dose finding phase, administered orally at a dose of 600mg or 800mg depending on tolerance, daily, cycles 1-12. For MZL, MCL or CLL patients in dose finding phase administered at an escalating dose from 20mg-400mg Cycle 1 on days 1-35, and at a dose of 400mg per day for Cycles 2-12. Patients in expansion phase will receive target dose established from dose finding cohorts daily for all 12 cycles.

Administered intravenously, starting at 1 mg/kg on second day of first cycle then 30mg/kg on days 8, 15 and 22 of cycle 1 and days 1 and 15 of cycles 2-12 for patients in both the dose finding and expansion phases.

Mark J Roschewski, M.D.

Background:

B-cell lymphoma is a cancer of certain white blood cells (called lymphocytes). These cells are found in lymph nodes. The cancer can cause enlargement of the lymph nodes leading to pain and discomfort. Swollen lymph nodes can also press on nearby organs such as liver and kidneys which can affect normal functioning of the organs. Researchers think that a new combination of drugs may be able to help.

Objective:

To find out if it is safe to give the combination of Magrolimab, Obinutuzumab and Venetoclax to people with B-cell lymphomas.

Eligibility:

Adults age 18 and older with an indolent B-cell lymphoma whose disease has returned or progressed after other treatment. Indolent B-cell lymphoma for this protocol is defined as having either follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma or marginal zone lymphoma.

Design:

Participants will be screened under a separate protocol.

Participants will have 28-day 'cycles' of treatment. They will take Venetoclax by mouth daily. They will get Obinutuzumab and Magrolimab by intravenous (IV) infusion. Treatment will last for about 8 months. They may be able to have more cycles of treatment if their cancer is responding well.

Participants will have physical exams, medical histories, and medicine reviews. Data about how they function in their daily activities will be obtained. They will have blood and urine tests. They may have bone marrow tests.

Participants will have imaging scans. These will include computed tomography (CT) and/or magnetic resonance imaging (MRI) scans and positron emission tomography (PET) scans.

Participants may give a cheek swab or saliva sample. They may give tumor tissue and bone marrow samples. These samples may be used for gene testing.

Participants will have a follow-up visit about 30 days after treatment ends. Then they will have visits every 3 months for the first 2 years, every 6 months for the next 3 years, and then yearly after that.

Background:

* Indolent B-cell malignancies are associated with frequent disease relapse
* Standard frontline therapy includes a monoclonal anti-CD20 antibody with or without chemotherapy; novel targeted therapies have changed the treatment landscape and are preferred therapy for some patients with high-risk molecular features
* Targeted therapies given indefinitely add to drug resistance, treatment-emergent toxicities, and non-compliance
* CD47 is a rational target for indolent B-cell malignancies; CD47 expression is higher in tumor cells than normal B-cells, and blocking CD47 results in phagocytosis of tumor cells
* Magrolimab is an anti-CD47 monoclonal antibody with activity in refractory indolent lymphomas when combined with rituximab (a first generation anti-CD20 monoclonal antibody)
* Obinutuzumab is a novel anti-CD20 monoclonal antibody with enhanced binding to the Fc receptor that may improve antibody-dependent cell-mediated cytotoxicity (ADCC), and phagocytosis, when combined with magrolimab
* We aim to test the safety and efficacy of venetoclax when added to the backbone of magrolimab and obinutuzumab in patients with relapsed or refractory indolent B-cell malignancies
* Treatment duration will be response-adapted and time-limited in all patients

Objective:

-To determine the safety of the triplet combination of venetoclax, magrolimab and obinutuzumab in relapsed and refractory indolent B-cell malignancies

Eligibility:

* Follicular lymphoma (FL) (grades 1-2, or 3a), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) with greater than or equal to 2 prior therapies, with at least one of those therapies containing an anti-CD20 monoclonal antibody
* ECOG performance status 0-2
* Adequate bone marrow and organ function

Design:

* Phase 1 study with expansion cohorts of up to 76 patients with relapsed or refractory FL, MZL, MCL or CLL
* The safety profile of magrolimab, venetoclax, and obinutuzumab will first be determined in a dose-finding phase of up to 24 patients (6-12 patients with FL and 6-12 patients with MZL, MCL or CLL). Patients without dose-limiting toxicity (DLT) will receive an additional 5 cycles (total 6 cycles) of the triplet combination.
* After dose-finding is completed, expansion cohorts of each histology will first receive magrolimab and obinutuzumab for 2 cycles in a window for translational research. After the window, venetoclax will be added and patients will receive 6 cycles (total 8 cycles) of the triplet combination.
* Patients who achieve a complete response (CR) (after a total of 6 cycles of the triplet combination) will stop treatment and initiate active monitoring with radiologic imaging and assays for circulating tumor DNA (ctDNA); if these patients relapse, they can be retreated with an 6 additional cycles. Patients who achieve partial response (PR) after 6 cycles of the triplet will continue for an additional 6 cycles; then, will initiate active monitoring.

Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies

A Phase 1 Study of Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies

.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Incidence of adverse events (i.e., grade and frequency)

Will be determined and reported from individual cohorts and histological diagnosis

Will be determined and reported along with a 95% confidence interval.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I/II Study of Different Doses and Dose Schedules of Milatuzumab (hLL1) in CLL	NCT00603668	Chronic Lymphoc...	milatuzumab	18 Years -	Gilead Sciences
Venetoclax With Obinutuzumab and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-cell Malignancies	NCT04599634	Follicular Lymp... Marginal Zone L... Mantle Cell Lym... Chronic Lymphoc... B-Cell Lymphoma	Obinutuzumab Venetoclax Magrolimab	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for chronic lymphocytic lymphoma