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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Lymphoma, Non-Hodgkin; Leukemia, Chronic Lymphocytic

Intervention / Treatment
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* Drug: LAM-002A
* Drug: Rituximab
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand and comply with the protocol requirements and has signed the informed consent document. 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. 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 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) Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or less. Adequate organ and marrow function. Able to swallow oral capsules without difficulty. Acceptable birth control. Women of childbearing potential : negative pregnancy test Adequate archival or fresh tumor tissue (from biopsy, bone marrow, or peripheral blood) for analysis of potential predictive biomarkers. Exclusion Criteria: 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. Not recovered from toxicity due to all prior therapies. Other uncontrolled significant illness. History of malabsorption or other gastrointestinal (GI) disease that may significantly alter the absorption of LAM-002A Major surgery within 28 days prior to first dose of study drug. Past history of tuberculosis (TB) or active infection with TB, human immunodeficiency virus (HIV), hepatitis B or hepatitis C. Lactation or breast feeding. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Continuous monotherapy<br>All patients will take LAM-002A two times daily by mouth every day until cancer progression or intolerability. | Drug: LAM-002A<br>* 25 mg capsules or 50 mg capsules<br>* Other names: apilimod dimesylate;|
| Experimental: Intermittent monotherapy<br>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<br>* 25 mg capsules or 50 mg capsules<br>* Other names: apilimod dimesylate;|
| Experimental: LAM-002A + rituximab<br>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<br>* 375 mg/m2 by vein<br>* Other names: rituxan;|
| Experimental: LAM-002A + atezolizumab<br>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<br>* 1200 mg by vein<br>* Other names: Tecentriq;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Safety, Apilimod dimesylate, Pharmacokinetics, Non-Hodgkin Lymphoma, Chronic lymphocytic leukemia