Phase I Dose-Escalation Study of AZD4785 in Patients With Advanced Solid Tumours

NCT03101839 | Completed Phase 1 FDA Drug

• 2 other identifiers: D8360C00001REFMAL 484
• Study Type: interventional
• Target: 28
• Locations: 2 countries
• Sites: 5

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.

Conditions

Non-Small Cell Lung Cancer; Advanced Solid Tumours

Keywords

AZD4785; KRAS; KRAS mutations; Non-small cell lung cancer; Advanced solid tumours

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD)

  Determined through the evaluation of dose-limiting toxicity (DLT), adverse events, clinical laboratory test results, clinical evaluation and patient reported symptoms

  Minimum of 28 days for a patient

Secondary Outcomes (4)

• 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.

• 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.

• KRAS messenger RNA (mRNA)

  1-3 months

Study Arms (1)

AZD4785

EXPERIMENTAL

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.

Drug: AZD4785

Interventions

AZD4785 DRUG

KRAS Antisense Oligonucleotide

AZD4785

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A Dose Escalation: Patients must have histological or cytological confirmation of a solid tumour known to harbour KRAS mutations (e.g., NSCLC, mCRC, pancreatic or cholangiocarcinoma), and have progressed despite standard therapy(ies), or are intolerant to standard therapy(ies), or have a tumour for which no standard therapy(ies) exists.
• Part B Expansion: Patients in Part B must have measurable disease as measured by Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1
• Group 1. Patients must have histological or cytological confirmation of locally advanced or metastatic KRASm+ NSCLC, who have failed prior therapy and for whom no current therapy is available.
• Group 2. Patients must have histological or cytological confirmation of locally advanced or metastatic KRASm+ NSCLC, who have failed prior therapy and for whom no current therapy is available. At study entry patients must be clinically suitable for mandatory baseline and on-treatment tumour biopsies.
• Signed written informed consent
• ≥ 18 years old
• All patients must have an activating KRAS mutation in tumour tissue samples from a prior test conducted by a clinical laboratory that has received international or country specific certification. Patients in Part B dosed on the basis of the local identification of an activating KRAS mutation, and whose KRAS mutation is not confirmed by the central laboratory (with the exception of locally obtained KRAS mutation status obtained from the approved tests), will remain on study but may be excluded from pharmacodynamic and anti-tumour activity analyses and replaced at the Sponsor's discretion. KRAS mutations identified in ctDNA (circulating tumour DNA) from blood are not acceptable; only mutations identified from tumour tissue are acceptable. Activating mutations may include but are not limited to:
• NSCLC KRAS mutations in codons G12/13, Q61, and A59
• mCRC KRAS mutations in codons G12/13 (Exon 2), Q61, A59 (Exon 3), K117, and A146 (Exon 4)
• Patient must agree to the collection of archival tumour tissue sample for biomarker analysis. If an archived tumour sample is not available a fresh tumour biopsy can be used.
• Adequate organ system function as indicated by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
• Platelets ≥ 100 x 10\^9/L
• Haemoglobin ≥ 9g/dL
• Activated partial thromboplastin time (aPTT) ≤ 1.5 times the upper limit of normal (ULN)

You may not qualify if:

• 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).
• Any of the following cardiac criteria:
• Congestive heart failure (CHF) per New York Heart Association (NYHA) classification \> Class II.
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Unstable angina or new-onset angina.
• QT interval (QTcF) \>470 ms on screening electrocardiogram (ECG) by Fridericia's formula.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (5)

Research Site

Sarasota, Florida, 34232, United States

Location

Research Site

Boston, Massachusetts, 02215, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

London, W1G 6AD, United Kingdom

Location

Research Site

Manchester, M20 4BX, United Kingdom

Location

Related Links

• Results of this clinical trial are available on www.astrazenecaclinicaltrials.com

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Hendrik-Tobias Arkenau, MD

  Sarah Cannon Research Institute United Kingdom

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 22, 2017
• First Posted: April 5, 2017
• Study Start: May 15, 2017
• Primary Completion: January 8, 2019
• Study Completion: January 8, 2019
• Last Updated: October 4, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (3); GB (2)