PQ203 in Advanced Malignant Tumors Including Triple Negative Breast Cancer

A Phase 1, Open-label, Multicenter Clinical Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics and Anti-Cancer Activity of PQ203 in Patients With Advanced Solid Tumor Malignancies

The primary purposes of this study are to determine the safety and tolerability of PQ203 in patients with advanced solid tumors including triple negative breast cancer (TNBC), and to determine a recommended Phase 2 dose level for future studies in TNBC.

This is an open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PQ203 in patients with selected advanced solid tumors. PQ203 will be administered as a once-weekly intravenous infusion.

The study consists of two parts: Phase 1A (dose escalation/expansion) and Phase 1B (dose optimization).

• Phase 1A will employ a dose-escalation design in patients with advanced solid tumors to assess the safety and tolerability of PQ203 as monotherapy and to establish a provisional Recommended Phase 2 Dose (RP2D). A dose-expansion component will further evaluate the provisional RP2D in one or more selected tumor types.
• Phase 1B will assess the provisional RP2D and further characterize safety, pharmacokinetics, and preliminary efficacy.

Endpoints:

• Primary Endpoints: Incidence of treatment-emergent adverse events (TEAEs) and determination of the RP2D.
• Secondary Endpoints: Pharmacokinetic profile of PQ203 and its payload (MMAE), and preliminary evidence of antitumor activity.

Inclusion Criteria:

• At least 18 years old
• Histologically or cytologically documented metastatic or locally advanced solid tumor malignancies having progressed through or being otherwise ineligible to receive approved standard-of-care therapies
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Documented presence of RECIST v1.1 measurable disease
• Adequate organ function confirmed by the following laboratory values obtained within 14 days of the first dose of PQ203:

Bone Marrow Function

• Absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L
• Platelets > 100 × 10e9/L
• Hemoglobin ≥ 9 g/dL

Hepatic Function

• AST, alanine transaminase ALT or ALP ≤ 2.5 × upper limit of normal (ULN); if liver metastases, then ≤ 5 × ULN
• Bilirubin ≤ 1.5 × ULN (< 2 × ULN if hyperbilirubinemia is due to Gilbert's syndrome)
• Serum albumin ≥ 35 g/L (3.5 g/dL)

Renal Function

• Calculated creatinine clearance of ≥ 60 mL/min by the Cockcroft-Gault equation
• Urine protein < 2+

Cardiac Function

• Left ventricular ejection fraction (LVEF) ≥ 50%

Other

• Understand and voluntarily sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/Research Ethics Board (REB)-approved informed consent form prior to any study-specific evaluation.
• PT/PTT or INR <1.2x upper limit of normal
• Non-surgically sterile men and women of child bearing potential must agree to use highly effective methods of contraception for at least 4 months beyond the final dose received.
• Toxicity of previous antitumor therapy has returned to Grade ≤1

Exclusion Criteria:

• Patients with primary central nervous system (CNS) malignancies (Patients with stable brain metastases (≥ 4 weeks after a treatment) not requiring steroids or other treatment will be allowed on study).
• Blood transfusion within 14 days of study treatment
• Serious comorbid medical conditions such as heart, lung, kidney, liver, and brain disease that, in the opinion of the enrolling investigator, could interfere with study treatment
• Subjects with history of severe heart disease
• QTc interval using Fridericia's formula (QTcF) > 470 ms
• Estimated or known weight > 115 kg (253 lbs)
• Known/suspected pregnancy and/or lactation
• Diastolic blood pressure < 60 mmHg or >110 mmHg
• Uncontrolled intercurrent illness
• Long term care facility resident or prisoner
• Any prior receipt of a MMAE-containing drug
• Any prior receipt of a SORT1-targeting medication
• Participation in another clinical study investigating a drug or medical device or a neuro-interventional or surgical procedure that is not considered as standard care in the 30 days preceding study enrolment
• Treatment with any of the following:
• Chemotherapy or other systemic anti-cancer therapy ≤14 days or 5 half-lives (whichever is shorter) prior to first dose of study drug except for Nitrosoureas or mitomycins ≤42 days
• Major surgery ≤28 days from first dose of study drug
• Patients with a history of cerebrovascular accident within 6 months of planned first dose.
• Patients with clinically symptomatic ocular toxicities
• Patients with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that require steroids, with current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Patients with active Grade >1 peripheral neuropathy