A Phase I/II, First-in-Human, Open Label, Dose Escalation and Expansion Study of AU-007, A Monoclonal Antibody That Binds to IL-2 and Inhibits IL-2Ra Binding, in Patients With Unresectable Locally Advanced or Metastatic Cancer
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Study Summary
To evaluate the safety, tolerability and immunogenicity of AU-007 as a monotherapy and in combination with aldesleukin in patients with unresectable locally advanced or metastatic cancer in solid tumours.
To evaluate the safety, tolerability, and initial efficacy of AU-007 in patients with advanced solid tumors.
To evaluate he safety, tolerability, and initial efficacy of AU-007 with or without aldesleukin, in patients with unresectable locally advanced or metastatic cancer.
Phase 2: To evaluate a dosing regimen selected from dose escalation for expansion in specified tumor types to further define the safety and initial efficacy of AU-007.
the safety, tolerability, immunogenicity and clinical activity of AU-007 in patients with unresectable locally advanced or metastatic cancer.
Phase 2 portion to assess AU-007 in combination with low-dose Proleukin®, with initial expansion cohorts planned in melanoma and renal cell carcinoma
To evaluate the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors
Phase 2 cohorts will evaluate AU-007 in combination with a single loading dose of low-dose, subcutaneous Proleukin (aldesleukin; recombinant human IL-2), or with AU-007 and low-dose, subcutaneous Proleukin administered every two weeks.
Phase 1: To evaluate AU-007 either as a monotherapy, in combination with a single loading dose of aldesleukin, or with both AU-007 and aldesleukin.
To evaluate the safety, tolerability, immunogenicity and clinical activity of AU-007 in patients with unresectable locally advanced or metastatic cancer.
Phase 1 consists of three dose escalation arms evaluating AU-007 either as a monotherapy, in combination with a single loading dose of recombinant human IL-2 (aldesleukin), or with both AU-007 and aldesleukin administered once every two weeks.
Phase 2 portion of the trial will evaluate a dosing regimen selected from dose escalation for expansion in specified tumor types to further define the safety and initial efficacy of AU-007.
To evaluate AU-007, a monoclonal antibody (mAb) that binds to IL-2 and inhibits CD25 binding, in patients with advanced solid tumors
Tumor assessments by computed tomography scan occur with each 8-week cycle. The AU-007 and aldesleukin dose and schedule for Phase 2 expansion will be based on safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD).
The dose-limiting toxicity (DLT) evaluation period is the first 28 days of the 1st cycle.
To demonstrate an overall trend in decreasing regulatory T cells (Tregs) and eosinophils, with encouraging early signs of anti-tumor activity.
To determine the phase 2 dose of AU-007.
Pharmacokinetic data was derived using standard antibody PK techniques. Circulating cell populations were determined by flow cytometry and both the cytokine and sCD25 levels were determined using electrochemoluminescence. Data from the assays were collated and compared across dosing regimens and levels.
The study consists of three dose escalation arms in patients with 19 solid tumor types followed by cohort expansion. Arm 1A evaluated escalating doses of AU-007 IV every 2 weeks (Q2W). Arm 1B evaluates 4.5 mg/kg AU-007 Q2W + escalating doses of one subcutaneous (SC) low dose of aldesleukin. Arm 1C evaluates escalating Q2W doses of AU-007 and SC low-dose aldesleukin.Cohort expansion evaluates 9 mg/kg AU-007 Q2W + 135K IU/kg aldesleukin dose once or Q2W, respectively, prioritizing melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC).
To evaluate AU-007 in Combination With Nivolumab for Second-Line Treatment of Melanoma
- 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 Must have objective progression after receiving at least two cycles of prior doublet therapy (anti-PD-1/anti-CTLA-4 or anti-PD-1/anti-LAG-3) Radiographic progression ≥ 4 weeks prior to the first dose of study drug to rule out late response to most recent therapy. The requirement for documented radiologic progression may be waived after review by Medical Monitor (e.g., in the case of progression beyond 12 weeks after starting a doublet) LDH ≤ 2.5 x ULN 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 Must have objective progression after receiving at least two cycles of prior doublet therapy (anti-PD-1/anti-CTLA-4 or anti-PD-1/anti-LAG-3). Radiographic progression ≥ 4 weeks prior to the first dose of study drug to rule out late response to most recent therapy. The requirement for documented radiologic progression may be waived after review by Medical Monitor (e.g., in the case of progression beyond 12 weeks after starting a doublet) LDH ≤ 2.5 x ULN 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
- 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
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