Study of AU-007, A Monoclonal Antibody That Binds to IL-2 and Inhibits IL-2Rα Binding, in Patients With Unresectable Locally Advanced or Metastatic Cancer

Study Overview
=================
Brief Summary
-----------------
This is a first in human, open-label, multi-center Phase 1 / 2 study to evaluate the safety, tolerability, and initial efficacy of AU-007 in patients with advanced solid tumors. AU-007 will be administered either as a monotherapy, or in combination with a single loading dose of aldesleukin, or with both AU-007 and aldesleukin given every 2 weeks (Q2w)

Detailed Description
-----------------
This is a first in human, multicenter, open-label Phase 1-2 study evaluating the safety, tolerability, and initial efficacy of AU-007 with or without aldesleukin, in patients with unresectable locally advanced or metastatic cancer. Patients must either be ineligible for or have progressed on prior standard of care therapy. Phase 1 consists of 3 escalation Arms, each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). The study begins in Arm A evaluating escalating doses of AU-007 (Q2w) in sequential escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). In Arm B, AU-007 (Q2w) is evaluated in combination with a single dose of aldesleukin given with the first AU-007 dose. AU-007 is administered at a fixed dose (Q2w) with an escalating single aldesleukin dose in sequential escalation cohorts. In Arm C, AU-007 is evaluated in combination with aldesleukin both given Q2w. AU-007 will be administered at a fixed dose with an escalating dose of aldesleukin in each sequential Arm C escalation cohort. The Phase 2, cohort expansion portion of the study consists of three expansion Arms evaluating the initial efficacy of the RP2D from corresponding dose escalation Arms A, B, and C in selected solid tumor types. Initially, melanoma and renal cell cancer will be evaluated in each Arm. Other eligible cancers include but not limited to Merkel Cell Carcinoma, non-small cell lung cancer and urothelial cancer.

Official Title
-----------------
A Phase 1/2, First-in-Human, Open Label, Dose Escalation and Expansion Study of AU-007, A Monoclonal Antibody That Binds to IL-2 and Inhibits IL-2Rα Binding, in Patients With Unresectable Locally Advanced or Metastatic Cancer

Conditions
-----------------
Advanced Solid Tumor, Metastatic Cancer

Intervention / Treatment
-----------------
* Drug: AU-007
* Drug: Aldesleukin


Participation Criteria
=================
Eligibility Criteria
-----------------
Selected Inclusion Criteria: Measurable or non-measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI. In Cohort Expansion, patients with truly non-measurable only disease (e.g., ascites, pleural or pericardial effusion, organomegaly), are not eligible for enrolment. In Dose Escalation patients must have selected tumor types and have progressed after standard of care treatment, or be intolerant to treatment, or refused standard treatment Female patients of childbearing potential must have a negative serum or urine pregnancy test performed within 72 hours prior to the initiation of study drug administration. Female patients of childbearing potential must be willing to use two forms of contraception throughout the study, starting with Screening through 60 days after the last dose of AU-007. Abstinence is acceptable if this is the established and the preferred contraception method for the patient Male patients with partners of childbearing potential must use barrier contraception from the time of consent through 60 days after discontinuation of AU-007 and must not donate sperm during this period. In addition, male patients should have their partners use contraception (as documented for female patients) for the same period of time Patients who have previously received an immune checkpoint inhibitor (e.g., anti-PD-L1, anti-PD-1, anti-CTLA-4) prior to enrollment must have checkpoint inhibitor immune-related toxicity resolved to either Grade ≤ 1 or baseline (prior to the checkpoint inhibitor) to be eligible for enrollment. Patients who experienced previous checkpoint inhibitor-related hypothyroidism are eligible for the study regardless of CTCAE grade resolution if well controlled on thyroid hormone replacement therapy Symptomatic central nervous system (CNS) metastases must have been treated, be asymptomatic for ≥ 14 days, and meet the following at the time of enrollment: No concurrent treatment for CNS disease (e.g., surgery, radiation, corticosteroids ≥ 10 mg prednisone/day or equivalent) No concurrent leptomeningeal disease or cord compression Exclusion Criteria: Patients with a history of known autoimmune disease with exceptions of Vitiligo Psoriasis, atopic dermatitis, or other autoimmune skin condition not requiring systemic treatment History of Graves' disease in patients now euthyroid for > 4 weeks Hypothyroidism managed by thyroid hormone replacement Alopecia Arthritis managed without systemic therapy beyond oral nonsteroidal anti- inflammatory drugs Major surgery or traumatic injury within 8 weeks before first dose of AU-007 Unhealed wounds from surgery or injury Treatment with > 10 mg per day of prednisone (or equivalent) or other immune-suppressive drugs within the 7 days prior to the initiation of study drug. Steroids for topical, ophthalmic, inhaled, or nasal administration are allowed Prior anti-cancer therapy before the planned start of AU-007 as follows: Not recovered to baseline from toxicity of prior systemic cancer therapy(ies). Not recovered from toxicity of radiotherapy. Concurrent use of hormones either to maintain castrate levels of testosterone in patients with castration-sensitive prostate cancer or for non-cancer-related conditions (e.g., insulin for diabetes, hormone replacement therapy) is acceptable. Bisphosphonates are permitted. Patients who have experienced SAEs during prior IL-2 therapy (including but not limited to bowel perforation, GI bleeding, arrythmias, MI, repetitive seizures). Inflammatory process that has not resolved for ≥ 4 weeks from the date of first study dose. Patients with chronic low-grade inflammatory processes such as radiation-induced pneumonitis are excluded regardless of duration Second primary invasive malignancy not in remission for ≥ 1 year. Exceptions include non-melanoma locally advanced skin cancer, cervical carcinoma in situ, localized prostate cancer (Gleason score ≤ 7), resected melanoma in situ, or any malignancy considered to be indolent and never required therapy, with the exception of indolent lymphomas

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: AU-007 Monotherapy<br>AU-007 (Q2w) will be administered as a monotherapy sequential ascending doses with each Dose Escalation Cohort | Drug: AU-007<br>* Monoclonal Antibody Targeting IL-2<br>|
| Experimental: AU-007 combined with an aldesleukin loading dose<br>AU-007 (Q2w) will be administered at a fixed dose in combination with a single dose of aldesleukin with the initial AU-007 dose. The aldesleukin dose will be escalated with each Dose Escalation Cohort | Drug: AU-007<br>* Monoclonal Antibody Targeting IL-2<br>Drug: Aldesleukin<br>* IL-2<br>|
| Experimental: AU-007 combined with aldesleukin given concomitantly<br>AU-007 will be administered at a fixed dose in combination with a aldesleukin, both administered Q2w. The aldesleukin dose will be escalated with each Dose Escalation Cohort | Drug: AU-007<br>* Monoclonal Antibody Targeting IL-2<br>Drug: Aldesleukin<br>* IL-2<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of AU-007 | Measured by the frequency of DLTs (Dose limiting Toxicity) and safety profile | Day 1 thru EOT visit (28 days after last dose) | 
| Establish the maximum tolerated dose (MTD) and or/ recommended Phase 2 dose (RP2D) | With AU-007 alone or in combination with aldesleukin measured by PK, PD, and Biomarkers | Day 1 thru EOT visit (28 days after last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Magnitude of Pharmacokinetic changes in the blood after dosing determined by area under the curve (AUC) of AU-007 | The AUC of AU-007 will be measured at different timepoints after AU-007 administration | Day 1 thru EOT visit (28 days after last dose) | 
| Magnitude of Pharmacokinetic changes in the blood after dosing determined by maximum concentration (Cmax) of AU-007 | The Cmax of AU-007 will be measured at different timepoints after AU-007 administration | Day 1 thru EOT visit (28 days after last dose) | 
| Magnitude of Pharmacokinetic changes in the blood after dosing determined by time of maximum concentration (Tmax) | The Tmax of AU-007 will be measured at different timepoints after AU-007 administration | Day 1 thru EOT visit (28 days after last dose) | 
| Magnitude of Pharmacokinetic changes in the blood after dosing determined by Half-life (T1/2) of AU-007 | The T1/2 of AU-007 will be measured at different timepoints after AU-007 administration | Day 1 thru EOT visit (28 days after last dose) | 
| Magnitude of cytokine changes in the blood after dosing |  | Day 1 thru EOT visit (28 days after last dose) | 
| Magnitude of immunogenicity after dosing with AU-007 alone or in combination with aldesleukin | Assessed by summarizing the number of patients who develop detectable anti-drug antibodies (ADAs) at different timepoints after AU-007 alone or in combination with aldesleukin | Day 1 thru EOT visit (28 days after last dose) | 
| Evaluate the preliminary anti-tumor activity of AU-007 alone or in combination with aldesleukin in patients with unresectable locally advanced or metastatic cancer | Clinical anti-tumor activity will be evaluated using conventional Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and modified RECIST v1.1. | Day 1 thru EOT visit (28 days after last dose) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IL-2 CD25, IL-2Ra, Clear cell renal cell cancer, Melanoma, Head and neck squamous cell carcinoma, Urothelial cancer, Gastric Cancer, Gastro-esophageal cancer, CD25, IL-2, NSCLC, Bladder Cancer, Merkel Cell Cancer, Proleukin, Immune Therapy, Immunotherapy, Cutaneous Squamous Cell Cancer, Cytokine