RTX-240 Monotherapy and in Combination With Pembrolizumab

Study Overview
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Brief Summary
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Open label, multicenter, multidose, first-in-human Phase 1/2 study of RTX-240 monotherapy or in combination of pembrolizumab for the treatment of patients with (1) relapsed/refractory R/R or locally advanced solid tumors (Phase 1/2) or (2) R/R Acute Myeloid Leukemia (AML) (Phase 1 only).

Detailed Description
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This is a Phase 1/2, open label, multicenter, multidose, first-in-human (FIH) dose escalation and expansion study to determine the safety and tolerability, recommended phase 2 dose and optimal dosing interval, pharmacology, and antitumor activity of RTX-240 in adult patients with relapsed/refractory (R/R) or locally advanced solid tumors (Phase 1/2) or R/R acute myeloid leukemia (Phase 1 only), and RTX-240 in combination with pembrolizumab in adult patients with R/R or locally advanced solid tumors (Phase 1 only). RTX-240 is a cellular therapy that co-expresses 4-1BBL and IL-15TP, a fusion of IL-15 and IL-15 receptor alpha, with the goal of stimulating the innate and adaptive immune systems for the treatment of cancer. The study includes a monotherapy dose escalation phase (Phase 1) followed by an expansion phase (Phase 2) in specified tumor types.

Official Title
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Phase 1/2 Study of RTX-240 Monotherapy and in Combination With Pembrolizumab

Conditions
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Solid Tumor, AML Adult

Intervention / Treatment
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* Drug: RTX-240
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent obtained prior to study procedures Patients ≥18 years with an ECOG 0 or 1 (Parts 1, 2 and 4) or 0-2 (Part 3). Relapsed/Refractory (R/R) or locally advanced, unresectable solid tumor for which no standard therapy exists (Parts 1, 2 and 4), or for which the patient is ineligible or has declined standard therapy or R/R, cytologically confirmed AML (Part 3). Disease must be measurable per Response Evaluation Criteria The shorter of 28 days or 5 half-lives must have elapsed since the completion of prior therapy, before initiation of study treatment. Adequate Organ Function and Blood Cell Counts (Parts 1, 2, and 4) as defined by the protocol: GFR ≥ 50 mL/min/1.73, AST and ALT ≤ 3 × the ULN and total bilirubin ≤ 1.5 × ULN, in the absence of cancer within the liver Or AST and ALT ≤ 5 × ULN and total bilirubin ≤ 3 × ULN, in the setting of primary or metastatic liver tumors. ANC ≥ 1 × 10^3/μL without myeloid growth factor support for at least one week prior to enrollment Platelet count ≥ 75 × 10^3/μL Hemoglobin should be ≥ 9 g/dL without red blood cell transfusion for at least one week Patients must have LVEF ≥ 45% Patients enrolling into Part 2 of the study must be diagnosed with NSCLC, RCC, or anal cancers Patients enrolling into Part 4 must be diagnosed with NSCLC or RCC Patients enrolling into either Part 2 or 4 must have 2 or fewer prior treatment regimens. If patient received a prior PD-1/PD-L1-containing regimen, a prior response is required. Exclusion Criteria: Primary central nervous system (CNS) malignancy or CNS involvement, unless asymptomatic, previously treated, and stable without steroids (Parts 1, 2 and 4) or known CNS leukemia (Part 3). Known hypersensitivity to any component of study treatment or excipients. Positive antibody screen using institution's standard type and screen test. Clinically significant, active and uncontrolled infection, including human immunodeficiency virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV). Clinically significant coagulopathy, uncontrolled hypertension or autoimmune hemolytic anemia Class III or IV cardiomyopathy per the New York Heart Association criteria Leukemic blast count ≥ 25 x 10^3/µL (Part 3) Concomitant conditions requiring active immunosuppression History of clinically significant Grade 3 or higher immune related Adverse Event (irAE) Prior malignancy within the past 3 years, with protocol specified exceptions History of severe hypersensitivity to a PD-1/PD-L1 blocking Ab unless previously rechallenged successfully (Part 4) Current noninfectious pneumonitis or a history of radiation pneumonitis or pneumonitis that required steroids, or Grade 2 or greater immune related pneumonitis, hepatitis, hypophysitis, or other endocrinopathy (Part 4)

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: RTX-240 Dose Escalation<br>Phase 1: RTX-240 monotherapy dose escalation in Solid Tumors | Drug: RTX-240<br>* Engineered red cells co-expressing 4-1BBL and IL-15TP<br>|
| Experimental: Part 2: RTX-240 Solid Tumor Expansion<br>Phase 2: RTX-240 monotherapy dose expansion in Non-small Cell Lung Cancer (NSCLC), Renal Cell Carcinoma (RCC), and anal cancers | Drug: RTX-240<br>* Engineered red cells co-expressing 4-1BBL and IL-15TP<br>|
| Experimental: Part 3: RTX-240 Dose Escalation<br>Phase 1: RTX-240 monotherapy dose escalation in AML | Drug: RTX-240<br>* Engineered red cells co-expressing 4-1BBL and IL-15TP<br>|
| Experimental: Part 4: RTX-240 Plus Pembrolizumab Dose Escalation<br>Phase 1: RTX-240 dose escalation in combination with Pembrolizumab in Solid Tumors | Drug: RTX-240<br>* Engineered red cells co-expressing 4-1BBL and IL-15TP<br>Drug: Pembrolizumab<br>* Humanized immunoglobulin G4 programmed death receptor-1 blocking antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Assessment: Measured by incidence of Treatment Emergent Adverse Events (TEAEs) |  | Up to 38 months | 
| Dose limiting toxicities (DLTs) of study treatment as determined by incidence and severity of adverse events (AEs) |  | Up to 38 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK of study treatment as measured by detection of the number of cells positive for both 4-1BBL and IL-15 using flow cytometry. |  | Assessed From the 1st dose of RTX-240 until 30 days after last of study treatment | 
| Determination of the Immunogenicity of study treatment Measured by the incidence of antibodies to RTX-240 |  | Assessed From the 1st dose of RTX-240 until 30 days after last of study treatment | 
| Anti-tumor activity of study treatment measured by clinical benefit rate (CBR) (% of patients who achieve CR, PR or stable disease [SD]) |  | Up to 38 months | 
| Anti-tumor activity of study treatment measured by duration of response (DoR) |  | Up to 38 months | 
| Anti-tumor activity of study treatment measured by progression free survival (PFS) |  | Up to 38 months | 
| Anti-tumor activity of study treatment measured by overall survival (OS) |  | Up to 38 months | 
| Anti-tumor activity of study treatment measured by time to response (TTR). |  | Up to 38 months | 
| Anti-tumor activity of study treatment measured by time to progression (TTP) |  | Up to 38 months | 
| Anti-Tumor activity of study treatment Measured by Objective Response Rate (ORR) |  | Up to 38 months | 
| Proportion of AML patients with CR, CR with incomplete recovery (CRi), morphologic leukemia-free state, or PR |  | Up to 38 months |