XTX202 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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A First-in-Human, Multicenter, Phase 1/2, Open-Label Study of XTX202 in Patients with Advanced Solid Tumors

Detailed Description
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This is a first-in-human, Phase 1/2, multicenter, open-label study designed to evaluate the safety, tolerability, and efficacy of XTX202, an engineered IL-2 prodrug with its activity masked, as monotherapy in patients with advanced solid tumors. Phase 1 Part 1a will examine XTX202 monotherapy in an accelerated and standard 3+3 dose-escalation design. Based on the results of Part 1a, Part 1b will be initiated to further examine XTX202 in patients with select advanced solid tumors and to further characterize XTX202. Based on results of Phase 1 patients with select advanced solid tumors will be enrolled in Phase 2.

Official Title
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A First-in-Human, Multicenter, Phase 1/2, Open-Label Study of XTX202 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: XTX202


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Criteria Phase 1, Part 1a: Any histologically or cytologically confirmed solid tumor malignancy that is locally advanced or metastatic and has failed standard therapy, or standard therapy is not curative or available Phase 1, Part 1b: Histologically or cytologically confirmed solid tumor malignancy with one of the following tumor histologies: RCC of clear cell histology only, melanoma, squamous cell skin carcinoma, ovarian cancer, non-small cell lung cancer. Those patients who previously received immunotherapy must have derived benefit from this treatment. Additionally, patients with any of the above histologies in an advanced setting who plan to undergo debulking surgery or oligometastasectomy may be eligible to receive 2 cycles of XTX202 treatment in a window of opportunity subcohort. Phase 2, Part 2a: Patients with metastatic RCC who have previously been treated with an anti-PD-1 and a TKI, per local and institutional SOC. Patients must have progressed on treatment with an anti-PD-1 mAb administered either as monotherapy or in combination with other therapies Phase 2, Part 2b: Patients with unresectable or metastatic melanoma who have previously been treated with at least 1 prior line of therapy in the recurrent or metastatic setting. Prior therapy must have included an anti-PD-1 alone or in combination per local and institutional standard of care, and patient must have progressed on checkpoint inhibitor therapy. Patients with BRAF V600-activating mutation must have previously received targeted therapy per local and institutional standard of care. ECOG performance status of 0 or 1 Adequate organ function Part 1b only patients must be willing to provide fresh tumor biopsies before and after initiation of study treatment. Exclusion Criteria: Received prior treatment with IL-2 therapy History of clinically significant pulmonary disease History of clinically significant cardiovascular disease Has a diagnosis of immunodeficiency Has an active autoimmune disease that has required systemic treatment in past 2 years, including the use of disease modifying agents, corticosteroids or immunosuppressive drugs Has an active infection requiring systemic therapy within 4 weeks prior to study treatment

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 XTX202 Dose Escalation and Pharmacodynamics Expansion<br>Part 1A Dose Escalation of XTX202 administered in ascending doses to patients with advanced or metastatic solid tumors to find the recommended phase 2 doses (RP2Ds). Part 1B Evaluation of XTX202 in patients with selected advanced solid tumors to further characterize the pharmacodynamic profile of XTX202 | Drug: XTX202<br>* XTX202 Monotherapy<br>|
| Experimental: Phase 2 XTX202 Dose Expansion<br>Part 2A will enroll patients with metastatic renal cell carcinoma who have progressed following standard-of-care treatment. Part 2B will enroll patients with melanoma who have progressed following standard-of-care treatment. | Drug: XTX202<br>* XTX202 Monotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) (Phase 1 Part 1A only) |  | Cycle 1 day 1 up to just prior to the second dose of study drug at Cycle 2 day 1 (each cycle is 21 days) | 
| Incidence of treatment-emergent adverse events (Phase 1 only) |  | Up to 24 months | 
| Incidence of changes in clinical laboratory values (Phase 1 only) |  | Up to 24 months | 
| Investigator-assessed objective response rate (ORR) per RECIST 1.1 (Phase 2 only) |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of XTX202 (total and intact) |  | Up to Cycle 7 (21 days per cycle) | 
| Maximum observed plasma concentration (Cmax) |  | Up to Cycle 7 (21 days per cycle) | 
| Time of maximum observed concentration (Tmax) |  | Up to Cycle 7 (21 days per cycle) | 
| Trough concentrations (Ctrough) |  | Up to Cycle 7 (21 days per cycle) | 
| Area under the curve (AUC) |  | Up to Cycle 7 (21 days per cycle) | 
| Half-life (T1/2) |  | Up to Cycle 7 (21 days per cycle) | 
| Systemic clearance (CL) |  | Up to Cycle 7 (21 days per cycle) | 
| Volume of distribution (Vd) |  | Up to Cycle 7 (21 days per cycle) | 
| Antidrug antibody (ADA) occurrence and titer in serum (Phase 1 only) |  | Up to 24 months | 
| Investigator-assessed objective response rate (ORR) per RECIST 1.1 (Phase 1 only) |  | Up to 24 months | 
| Duration of response (DOR) (Phase 2 only) |  | Up to 24 months | 
| Disease control rate (Phase 2 only) |  | Up to 24 months | 
| Progression-free survival (PFS) (Phase 2 only) |  | Up to 24 months | 
| Overall survival (OS) (Phase 2 only) |  | Up to 24 months | 
| Incidence of treatment-emergent adverse events (Phase 2 only) |  | Up to 24 months | 
| Incidence of changes in clinical laboratory values (Phase 2 only) |  | Up to 24 months |