A Phase I, Open-Label, Multicentre Dose-Escalation Study to Investigate the Safety and Pharmacokinetics of AZD4785 in Patients With Advanced Solid Tumours Where KRAS May Be an Important Driver of Tumour Survival
Overview
- Phase
- Phase 1
- Intervention
- AZD4785
- Conditions
- Non-Small Cell Lung Cancer
- Sponsor
- AstraZeneca
- Enrollment
- 28
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
A Phase I, open-label, multicentre, dose-escalation study to investigate the safety, pharmacokinetics and maximum tolerated dose (MTD) of AZD4785 in patients with advanced solid tumours where KRAS may be an important driver of tumour survival.
Part A: Dose escalation in patients with solid tumours to evaluate safety, pharmacokinetics and maximum tolerated dose (MTD). Once the maximum tolerated dose (MTD) is established, a dose expansion cohort may be included in Part A, with up to an additional 6 patients to further explore the PK, safety, tolerability, and preliminary anti-tumour activity of the AZD4785 MTD for confirmation of the recommended phase 2 dose (RP2D).
Part B: Expansion cohort at the selected dose in patients with non-small cell lung cancer (NSCLC) to evaluate PK parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD4785 RP2D as monotherapy in patients with NSCLC. Approximately 20 patients with NSCLC (Two groups of approximately 10 patients each) with NSCLC will be enrolled to Part B. Group 1 patients will have an option to provide tumour biopsies and Group 2 will be required (mandatory) to provide paired tumour biopsies. Overall up to 12 patients in Group 2Part B patients will be required (mandatory) to may provide paired tumour biopsies. A third group of up to 20 patients with other tumour types and/or a potential different schedule may be added based on the results seen in Parts A and B and any other emerging data and may also provide biopsies.
Detailed Description
This is a First-Time-in-Human (FTIH), Phase 1 study to determine the MTD, recommended Phase 2 dose (RP2D), safety, tolerability, pharmacodynamics, and pharmacokinetics of AZD4785. The study will be conducted in two parts: a dose-escalation phase (Part A)and an expansion phase (Part B). A third group of up to 20 patients with other tumour types and/or a potential different schedule may be added based on the results seen in Parts A and B and any other emerging data. AZD4785 will be given as an IV infusion over 1 hour, initially in 3 loading doses during the first week and then weekly thereafter. The loading doses will be given on Days 1, 3, and 5 of the first week and weekly thereafter on Days 8, 15, and 22 of 28 Day cycles. In subsequent cycles AZD4785 will be administered on Days 1, 8, 15, and 22 until disease progression, intolerable toxicity, or discontinuation criteria have been met. Once the MTD is established, a dose expansion cohort may be included in Part A, with up to 6 additional patients to explore the PK, safety, tolerability, and preliminary anti-tumour activity of the AZD4785 MTD for confirmation of the RP2D. Thereafter, Part B expansion phase will continue to explore PK parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD4785 RP2D as monotherapy in patients with NSCLC. Approximately 20 patients with NSCLC (2 groups of approximately 10 patients each) with NSCLC will be enrolled to Part B. Group 1 patients will have an option to provide tumour biopsies and Group 2 will be required (mandatory) to provide paired tumour biopsies. Overall up to 12 patients in Part B may provide paired tumour biopsies. A third group of up to 20 patients with other tumour types and/or a potential different schedule may be added based on the results seen in Parts A and B and any other emerging data and may also provide biopsies. Up to 12 patients in Part B may provide paired biopsies.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- •Patients who have received chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational drugs within 21 days or 5 half lives (whichever is shorter) from enrolment.
- •With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of enrolment.
- •Unresolved immunotherapy-related hepatotoxicity from previous therapy.
- •Major surgery (excluding placement of vascular access) ≤ 21 days from beginning of the enrolment or minor surgical procedures ≤ 7 days. No waiting is required following implantable port and catheter placement.
- •Patients receiving full-dose anti-coagulation therapies.
- •Has active or prior documented autoimmune disease within the past 2 years with the exception of vitiligo, Grave's disease, and/or psoriasis not requiring systemic treatment.
- •Has a history of atypical Haemolytic Uremic Syndrome.
- •Patients with leptomeningeal metastases.
- •Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 3 weeks prior to enrolment and there is no evidence of central nervous system disease progression or mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.
- •Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
Arms & Interventions
AZD4785
This is a single-arm study in which all patients will receive AZD4785 by IV infusion. Patients will continue to receive treatment with AZD4785 until disease progression, intolerable toxicity, or discontinuation criteria are met.
Intervention: AZD4785
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD)
Time Frame: Minimum of 28 days for a patient
Determined through the evaluation of dose-limiting toxicity (DLT), adverse events, clinical laboratory test results, clinical evaluation and patient reported symptoms
Secondary Outcomes
- Area under the plasma concentration versus time curve (AUC) for AZD4785(Samples for determination of AZD4785 plasma conc. will be collected at multiple times on Day 1 Cycle 1, pre-dose on Days 3, 5, and 8 of Cycle 1, Day 22 of Cycle 2, and Day 1 of Cycles 3 and 4. Time points may be adjusted based on emerging data.)
- Objective Clinical Response(Every 8 weeks up to 12 months.)
- Peak plasma concentration (Cmax) of AZD4785(Samples for determination of AZD4785 plasma conc. will be collected at multiple times on Day 1 Cycle 1, pre-dose on Days 3, 5, and 8 of Cycle 1, Day 22 of Cycle 2, and Day 1 of Cycles 3 and 4. Time points may be adjusted based on emerging data.)
- KRAS messenger RNA (mRNA)(1-3 months)