A Phase I Trial of Vandetanib (AZD6474) and Selumetinib (AZD6244) for Solid Tumours Including Non Small Cell Lung Cancer (VanSel-1)

NCT01586624 | Completed Phase 1 Results

• 2 other identifiers: CRUKD/11/0012011-000627-33
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 4

Brief Summary

The purpose of this study is to determine whether using two drugs together called vandetanib and selumetinib is effective in the treatment of cancer. The first part of this study will include patients with any solid tumour and the second part of this study will include only patients with non small cell lung cancer. The four main aims of this clinical study are to find out:

• If the two drugs can be given safely to patients when given together.
• The maximum dose that can be given safely to patients.
• More about the potential side effects of the drugs and how they can be managed.
• What happens to vandetanib and selumetinib inside the body.

Conditions

Cancer; Non Small Cell Lung Cancer

Keywords

Phase I; Drug evaluation; Oncology; Vandetanib; Selumetinib; Dose escalation; Clinical trial; Vascular Endothelial Growth Factor (VEGFR) inhibitor; Epidermal Growth Factor Receptor (EGFR) inhibitor; Mitogen Activated Kinase (MEK) inhibitor; Non small cell lung cancer

Outcome Measures

Primary Outcomes (2)

• Number of Serious Adverse Events, Non-serious Adverse Events and Treatment Emergent Adverse Events.

  Number of serious adverse events, non-serious adverse events and treatment emergent adverse events.

  Safety data was collected from the date of written informed consent and continued until 28 days after the final administration of vandetanib and selumetinib, an average (mean) of 164 days (approximately 5.4 months).

• Number of Dose Limiting Toxicities (DLTs) Within Each Cohort.

  Number of DLTs within each cohort.

  DLTs occurring in the first Cycle (up to Day 42).

Secondary Outcomes (8)

• Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Vandetanib.

  0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

• Dose Escalation Cohorts Only: PK Parameter Maximum Observed Plasma Concentration of Selumetinib.

  0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

• Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-24 Hours) of Vandetanib.

  0 hours (pre dose) and at 0.5, 2, 4, 6 and 24 hours post dose on Day 4. 0 hours (pre dose) and at 0.5, 2, 4, 6, 10 and 24 hours post dose on Days 15 and 29.

• Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of Selumetinib.

  0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.

• Dose Escalation Cohorts Only: PK Parameter Area Under the Plasma Concentration Time Curve (0-12 Hours) of N-desmethyl Metabolite of Selumetinib.

  0 hours (pre dose) and at 0.5, 2, 4, 6 and 10 hours post dose on Days 15 and 29.

Study Arms (8)

Dose Escalation Phase Cohort 1 (Steady state dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)

EXPERIMENTAL

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib

Dose Escalation Phase Cohort 2 (Steady state dose of 100 mg OD Vandetanib + 50 mg BD Selumetinib)

EXPERIMENTAL

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib

Dose Escalation Phase Cohort 3 (Steady state dose of 100 mg OD Vandetanib + 75 mg BD Selumetinib)

EXPERIMENTAL

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib

Dose Escalation Phase Cohort 4 (Steady state dose of 100 mg OD Vandetanib + 100 mg OD Selumetinib)

EXPERIMENTAL

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib

Dose Escalation Phase Cohort 5a (Steady state dose of 100 mg OD Vandetanib + 125 mg OD Selumetinib)

EXPERIMENTAL

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib

Dose Escalation Phase Cohort 5b (Steady state dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)

EXPERIMENTAL

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib

Dose Escalation Phase Cohort 6 (Steady state dose of 300 mg OD Vandetanib + 50 mg BD Selumetinib)

EXPERIMENTAL

Dose escalation to determine recommended dose and schedule for Phase 2 evaluation of vandetanib and selumetinib.

Drug: Vandetanib, Selumetinib

Expansion Phase (Steady state dose of 200 mg OD Vandetanib + 50 mg BD Selumetinib)

EXPERIMENTAL

Expansion cohort at the recommended phase 2 dose of vandetanib and selumetinib defined in the escalation phase.

Drug: Vandetanib, Selumetinib

Interventions

Vandetanib, Selumetinib DRUG

Cycle 1: Vandetanib higher (lead in) dose of 300 mg OD (Days 1 to 4) followed by vandetanib steady state dose of 100 mg OD (Days 5 to 14) followed by vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). Cycle 1 is 42 days long. Cycle 2 onwards: Vandetanib steady state dose of 100 mg OD + 25 mg of selumetinib BD (28 days). From Cycle 2, cycles are 28 days long. Patients will be allowed to receive 6 cycles. If the patient is still benefiting clinically with no unacceptable toxicity, then the Investigator can ask the Sponsor for continuation of treatment.

Dose Escalation Phase Cohort 1 (Steady state dose of 100 mg OD Vandetanib + 25 mg BD Selumetinib)

Eligibility Criteria

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

You may qualify if:

• (Dose escalation cohorts) Histologically or cytologically proven solid tumour for which no conventional therapy exists or is declined by the patient
• (Expansion cohort only) Histologically or cytologically confirmed NSCLC patients only, for which no conventional therapy exists or is declined by the patient.
• If only cytologically confirmed, baseline biopsy is mandatory for a patient to be eligible.
• For NSCLC patients to be eligible for the expansion cohort they must have received:
• One prior line of chemotherapy and/or
• Previous platinum based chemotherapy and/or
• At least one previous EGFR inhibitor
• (Expansion cohort only) Measurable disease according to RECIST criteria Version 1.1 in final version of the protocol
• Life expectancy of at least 12 weeks
• World Health Organisation (WHO) performance status of 0-1
• Baseline LVEF \> 50%
• Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day -1) before the patient goes on study.
• Laboratory Test Value required
• Haemoglobin (Hb) ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 10\^9/L

You may not qualify if:

• Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous 4 weeks (6 weeks for investigational medicinal products) before treatment.
• Patients who have been withdrawn from treatment with agents that target EGFR because of unacceptable toxicity (prior treatment with these agents is allowed) and those patients who have had EGFR dose reductions by 50% or more.
• Expansion cohort only: Prior treatment with any agent that targets MEK or VEGFR
• Any prior exposure to RAS or RAF inhibitors
• Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 2 toxicities, which in the opinion of the Investigator and the Centre for Drug Development (CDD) should not exclude the patient.
• Symptomatic brain metastases (patients must be stable for \>3 months post RT treatment) or spinal cord compression.
• Patients with interstitial lung disease.
• Pregnant or lactating women are excluded. Female patients with the ability to become pregnant who have a negative serum or urine pregnancy test before enrollment and agree to use two of the following three highly effective forms of combined contraception (oral, injected or implanted hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
• Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception \[condom plus spermicide\] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
• Major surgery from which the patient has not yet recovered.
• At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
• Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).
• Cardiac conditions as follows:
• Clinically significant cardiovascular event within 3 months prior to entry to include:
• Myocardial infarction

Sponsors & Collaborators

• Cancer Research UK: lead
• AstraZeneca: collaborator

Study Sites (4)

Churchill Hospital

Headington, Oxford, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

The Christie Hospital

Manchester, United Kingdom

Location

Freeman Hospital

Newcastle, United Kingdom

Location

Related Links

• Simple summary of trial results on Cancer Research UK Trial Database

MeSH Terms

Conditions

Neoplasms; Carcinoma, Non-Small-Cell Lung

Interventions

vandetanib; AZD 6244

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

61 patients were enrolled. 3 withdrew before having vandetanib (Van) or selumetinib (Sel). 1 patient in Cohort 5b received Van but withdrew before having Sel and was excluded from the safety analysis. The remaining 57 patients had at least 1 dose of the combination and were included in the safety analysis population (46 in dose escalation, 11 in expansion). PFS was planned to be assessed at 12 weeks but was instead assessed at 10 and 18 weeks as disease assessments were performed every 2 cycles

Results Point of Contact

• Title: Regulatory Affairs Manager
• Organization: Cancer Research UK Centre for Drug Development

regulatory@cancer.org.uk

+44 203 4696878

Study Officials

• Denis Talbot, Prof

  Oxford University Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Study Record Dates

• First Submitted: April 25, 2012
• First Posted: April 27, 2012
• Study Start: January 10, 2012
• Primary Completion: June 11, 2020
• Study Completion: June 11, 2020
• Last Updated: October 7, 2021
• Results First Posted: October 7, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (4)