PQ203 in Advanced Malignant Tumors Including Triple Negative Breast Cancer

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