A Phase I Dose Escalation Study of the Safety and Pharmacokinetics of LAM-002A In Patients With Non-Hodgkin's Lymphoma (LAM-002A/NHL) (LAM-002A/NHL)

A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of LAM-002A (Apilimod Dimesylate Capsules) Administered Orally in Subjects With Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

This is a Phase 1 dose-exploration study of LAM-002A administered by mouth in patients with relapsed or refractory B-cell NHL. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD),and preliminary anti-tumor activity will be evaluated.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Non-Hodgkin; Leukemia, Chronic Lymphocytic
• Intervention / Treatment: Drug: Rituximab; Drug: LAM-002A; Drug: Atezolizumab

Detailed Description

LAM-002A is supplied as 25-mg or 50-mg capsules and will be administered two times daily or three times daily by mouth in repeated 28-day cycles. Patients will be advised to take the doses at the same time each day.

A 3 + 3 design will be utilized to define a maximum tolerated dose (MTD). The MTD is defined as the highest dose at which no more than 1 of 6 patients (i.e., < 33%) experiences a dose-limiting toxicity (DLT) in the dose cohort.

Once the dose and schedule are established, additional patients will be treated to better characterize the safety, tolerability,PK, PD, and anti-tumor activity of LAM-002A when administered alone or in combination with rituximab or atezolizumab.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Huntsville, Alabama, United States, 35805
      • Clearview Cancer Institute
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute at Emory University
  • Indiana
    • Lafayette, Indiana, United States, 47905
      • Horizon Oncology Research, Inc.
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10016
      • New York University School of Medicine
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Able to understand and comply with the protocol requirements and has signed the informed consent document.
2. Confirmed diagnosis of B-cell Non-Hodgkin's lymphoma limited to follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), primary mediastinal B-cell lymphoma (PMBL), or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that has progressed and for which standard curative measures do not exist or are no longer effective. Prior therapy must have included a rituximab-based regimen.
3. Patients with DLBCL: Cancer progression after transplant, or be unwilling, unable or not an appropriate candidate for an autologous stem cell or bone marrow transplant
4. Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of 1 or more lesions that measure at least 2.0 cm in the longest dimension (as assessed radiographically)
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or less.
6. Adequate organ and marrow function.
7. Able to swallow oral capsules without difficulty.
8. Acceptable birth control.
9. Women of childbearing potential : negative pregnancy test
10. Adequate archival or fresh tumor tissue (from biopsy, bone marrow, or peripheral blood) for analysis of potential predictive biomarkers.

Exclusion Criteria:

1. Patients with central nervous system (CNS) lymphoma are not eligible for the trial unless the disease had been treated and the subject remains without symptoms with no active CNS lymphoma.
2. Not recovered from toxicity due to all prior therapies.
3. Other uncontrolled significant illness.
4. History of malabsorption or other gastrointestinal (GI) disease that may significantly alter the absorption of LAM-002A
5. Major surgery within 28 days prior to first dose of study drug.
6. Past history of tuberculosis (TB) or active infection with TB, human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
7. Lactation or breast feeding.
8. Unable or unwilling to abide by the study protocol or cooperate fully with the Investigator or designee.

This is a shortened list and additional criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Continuous monotherapy; All patients will take LAM-002A two times daily by mouth every day until cancer progression or intolerability.	Drug: LAM-002A; 25 mg capsules or 50 mg capsules; Other Names: apilimod dimesylate
Experimental: Intermittent monotherapy; All patients will receive LAM-002A at escalating dose levels two times daily by mouth for 3 days on therapy followed by 4 days off therapy every week until cancer progression or intolerability.	Drug: LAM-002A; 25 mg capsules or 50 mg capsules; Other Names: apilimod dimesylate
Experimental: LAM-002A + rituximab; All patients will receive LAM-002A 125mg two times daily by mouth every day until cancer progression or intolerability and rituximab 375 mg/m2 by vein every week for 4 weeks and then every 8 weeks for 4 times (total of 8 infusions)	Drug: Rituximab; 375 mg/m2 by vein; Other Names: rituxan
Experimental: LAM-002A + atezolizumab; All patients will receive LAM-002A 125mg two times daily by mouth every day until cancer progression or intolerability and atezolizumab 1200 mg by vein every 3 weeks until cancer progression or intolerability	Drug: Atezolizumab; 1200 mg by vein; Other Names: Tecentriq

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the MTD of oral LAM-002A	Dose escalation until determination of DLTs	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Plasma Concentration (Cmax) of LAM-002A	Evaluation of LAM-002A and its metabolites in plasma	28 days
Area under the plasma concentration versus time curve (AUC) of LAM-002A	Evaluation of LAM-002A and its metabolites in plasma	28 days
Type and frequency of adverse events and serious adverse events as assessed by CTCAE v4.0	Identify toxicities	1 cycle (28 days) to 6 or more cycles
Anti-tumor response as assessed by investigator according to modified Hallek or Lugano Response Criteria	Evaluation of the ability of LAM-002A to shrink tumors	1 cycle (28 days) to 6 or more cycles

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microscopic changes in the internal structure of tumor cells and white blood cells	Determine the effect of LAM-002A on tumor cells and blood samples	1 cycle (28 days) to 2 cycles
Evaluation of genetic alterations and expression in tumor	Determine potential genetic make-up of NHL tumors	1 cycle (28 Days) to 2 cycles
Evaluation of immune modulatory effects of LAM-002A	Determine immune modulation activity of LAM-002A	1 cycle (28 days) to 2 cycles
Plasma identification of analytes	Preliminary assessment of anti-lymphoma activity	1 cycle (28 days)

Collaborators and Investigators

• Sponsor: AI Therapeutics, Inc.
• Investigators: Study Director: Langdon Miller, MD, AI Therapeutics

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): March 9, 2020
• Study Completion (Actual): March 30, 2023

Study Registration Dates

• First Submitted: October 29, 2015
• First Submitted That Met QC Criteria: October 30, 2015
• First Posted (Estimated): November 3, 2015

Study Record Updates

• Last Update Posted (Actual): July 19, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Phase 1; Non-Hodgkin Lymphoma; Chronic lymphocytic leukemia; Apilimod dimesylate
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Chronic Disease; Lymphoma; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Rituximab; Atezolizumab
• Other Study ID Numbers: LAM-002A-NHL-CLN01