RTX-240 Monotherapy and in Combination With Pembrolizumab

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).

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.

Eligibility Criteria:
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)