Clinical trial NCT05267626: 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumor
Metastatic Cancer
Cutaneous Melanoma
Non-Small Cell Lung Cancer
Keywords: IL-2 CD25
IL-2Ra
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
Anti-PD-L1
Non-small cell lung cancer
Clear cell renal cell cancer
Lead sponsor: Aulos Bioscience, Inc.
Sponsor class: INDUSTRY
First posted: 2022-03-04
Enrollment: 159
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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). Once the recommended phase 2 dose (RP2D) of AU-007 plus aldesleukin was determined, (AU-007 Q2w plus a single loading dose of aldesleukin), AU-007 plus aldesleukin is also being administered with avelumab or nivolumab.

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.

Part 1 consists of 3 escalation Arms, each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the 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 RP2D or 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 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 with an escalating dose of aldesleukin in each sequential Arm C escalation cohort.

The Part 2 cohort expansion portion of the study consists of up to three expansion Arms evaluating the initial efficacy of the RP2D (AU-007 plus a single loading dose of aldesleukin) in selected solid tumor types, prioritizing cutaneous melanoma and non-small cell lung cancer (NSCLC).

Part 3 evaluates the safety of AU-007 in combination with aldesleukin and avelumab, followed by one expansion cohort, in NSCLC.

Part 4 evaluates the safety of AU-007 plus aldesleukin in combination with nivolumab, followed by one expansion cohort, in cutaneous melanoma.

Eligibility criteria: Selected Inclusion Criteria:

* Patients must have measurable disease as per RECIST v1.1 criteria and documented by CT and/or MRI

Part 2 includes but is not limited to:

* Cutaneous melanoma that is either locally unresectable or metastatic:

  * BRAF wild type: progressed after receiving PD-1 containing therapy with or without an anti-CTLA-4
  * BRAF mutation: patients who refused BRAF+MEK inhibitor
* NSCLC: Unresectable locally advanced or metastatic PD-L1-positive (tumor proportion score \[TPS\] ≥ 1%) NSCLC not harboring an activating EGFR mutation or ALK rearrangement and has progressed during or following treatment with an anti-PDx with or without platinum-based chemotherapy

Part 3: NSCLC as described above

Part 4: cutaneous melanoma

* Unresectable locally advanced or metastatic cutaneous melanoma that has progressed during or following treatment with an anti-PDx (unless ineligible for anti-PDx therapy)
* Patients with BRAF mutations must either be ineligible for or have refused a BRAF+MEK inhibitor
* Patients must have no more than 1 prior line of systemic therapy for unresectable locally advanced or metastatic disease. Neo-adjuvant and adjuvant therapy do not count as a prior line of therapy

  * 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 study drug (or 5 months after the last dose of study drug for patients receiving nivolumab). 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 study drug 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 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 3 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 serious adverse events during prior IL-2 therapy (including but not limited to bowel perforation, gastrointestinal bleeding, arrythmias, myocardial infarction, 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

Primary outcomes:
measure: Evaluate the safety and tolerability of AU-007
timeFrame: Day 1 thru end of treatment (EOT) visit (28 days after last dose)
measure: Establish the maximum tolerated dose (MTD) and/or RP2D
timeFrame: Day 1 thru EOT visit (28 days after last dose)
Secondary outcomes:
measure: Magnitude of PK changes in the blood after dosing determined by area under the curve (AUC) of AU-007
timeFrame: Day 1 thru EOT visit (28 days after last dose)
measure: Magnitude of PK changes in the blood after dosing determined by maximum concentration (Cmax) of AU-007
timeFrame: Day 1 thru EOT visit (28 days after last dose)
measure: Magnitude of PK changes in the blood after dosing determined by time of maximum concentration (Tmax)
timeFrame: Day 1 thru EOT visit (28 days after last dose)
measure: Magnitude of PK changes in the blood after dosing determined by Half-life (T1/2) of AU-007
timeFrame: Day 1 thru EOT visit (28 days after last dose)
measure: Magnitude of cytokine changes in the blood after dosing
timeFrame: Day 1 thru EOT visit (28 days after last dose)
measure: Magnitude of immunogenicity after dosing with AU-007 alone or in combination with aldesleukin, AU-007 in combination with aldesleukin and avelumab or nivolumab
timeFrame: Day 1 thru EOT visit (28 days after last dose)
measure: Evaluate the preliminary anti-tumor activity of AU-007 alone, in combination with aldesleukin, in combination with aldesleukin and avelumab, and AU-007 plus aldesleukin with nivolumab in patients with unresectable locally advanced or metastatic cancer
timeFrame: Day 1 thru EOT visit (28 days after last dose)
Other outcomes:
Locations:
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: Huntersville
country: United States
facility: Carolina Biooncology Institute
state: North Carolina
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: START South Texas Accelerated Research Therapeutics
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Huntsman Cancer Institute
state: Utah
city: Miranda
country: Australia
facility: Southside Cancer Care Centre
state: New South Wales
city: Bedford Park
country: Australia
facility: Southern Oncology Clinical Research Unit
state: South Australia
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Frankston
country: Australia
facility: Peninsula & South Eastern Haematology and Oncology Group
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Saint Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
Study officials:
affiliation: Aulos Bioscience, Inc.
name: James Vasselli, MD
role: STUDY_CHAIR
References: