Phase I/II Trial of Antagonism of HER in GI Cancer

Study Overview
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Brief Summary
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Recruitment to phase I of the PANTHER trial is complete. Phase II, is to evaluate the best overall response rate for AZD8931 + FOLFIRI treatment.

Detailed Description
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PANTHER is a registered phase I/phase II trial in patients with recurrent or metastatic colorectal cancer. The phase II part of the study will be a single arm trial. Patients will receive AZD8931 (an EGFR/ERBB inhibitor) in combination with FOLinic acid, Fluorouracil and IRInotecan (FOLFIRI), Treatment will be given in two-weekly cycles. Phase II's primary objective is to evaluate the Best overall response

Official Title
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AZD8931, an Inhibitor of EGFR, ERBB2 and ERBB3 Signalling, in Combination With FOLFIRI: a Phase I/II Study to Determine the Importance of Schedule and Activity in Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer, Recurrent Colorectal Cancer

Intervention / Treatment
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* Drug: AZD8931
* Drug: Irinotecan
* Drug: Folinic Acid
* Drug: Fluorouracil
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathological/cytological diagnosis of non-resectable, recurrent or metastatic colorectal cancer Tumour with wild-type RAS Measurable disease evaluated by RECIST criteria v1.1 WHO performance status 0 or 1 Age ≥ 16 Estimated life expectancy > 3 months Adequate haematological function: Haemoglobin ≥100 g/L Absolute neutrophil count ≥1.5 x 10^9/L Platelet count ≥100 x 10^9/L Adequate liver function: Total bilirubin ≤1.5 x upper limit of normal (ULN) (except for patients with known documented cases of Gilbert's syndrome) ALT, AST & ALP ≤2.5 x ULN in the absence of noted liver metastases ALT, AST & ALP ≤5 x ULN in the presence of liver metastases Adequate renal function: Serum creatinine ≤1.5 x ULN Calculated creatinine clearance ≥30 mL/min Adequate biliary drainage (patients with stents are eligible) Adequate venous access for collection of exploratory biological samples Women of child-bearing potential must have a negative pregnancy test prior to study entry. Female patients and male patients with partners of child-bearing potential must agree to use an adequate contraception method, which must be continued for 6 months after completion of chemotherapy Must be able to swallow AZD8931 tablets Capable of giving written informed consent The following prior therapy is allowed: Surgery - patients may have undergone a non-curative operation or palliative bypass surgery only. Patients who have previously undergone curative surgery must have evidence of non-resectable disease relapse Radiotherapy - for localised disease Prior adjuvant chemotherapy - provided this was completed at least 6 months before trial entry Exclusion Criteria: Patients undergoing treatment with curative intent Any prior treatment with agents targeting the ERBB pathway Treatment with experimental drugs within 30 days or 5 half-lives of first dose of AZD8931 Previous palliative chemotherapy Prior treatment with anthracyclines or mitoxantrone Current disease or condition known to interfere with absorption, distribution, metabolism or excretion of drugs (including refractory nausea and vomiting, chronic gastrointestinal disease (e.g. inflammatory bowel disease), or significant bowel resection) History of prior malignancy that will interfere with the response evaluation (exceptions listed in protocol) Evidence of severe/uncontrolled systemic diseases or laboratory finding that makes it undesirable for the patient to participate in the trial Evidence of active uncontrolled infection Patients with clinically significant ascites and/or effusions Regular use of anti-diarrhoeal Pregnant or lactating women Cardiac conditions (as detailed in the trial protocol) Any psychiatric or other disorder (e.g. brain metastases) likely to impact the ability to give informed consent Eye conditions (as detailed in the trial protocol) Patients with chronic skin conditions e.g. acne rosacea, psoriasis, severe atopic eczema Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease History or repeated unexplained episodes of syncope/dizziness Known hypersensitivity to AZD8931, its excipients, or drugs in its class The use of drugs/substances known to inhibit or induce CYP3A4 or CYP2D6, or those known to prolong QT interval, which cannot be discontinued for the duration of trial treatment Patients with hereditary fructose intolerance

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>AZD8931 160 mg bd, on days 1-4, + FOLFIRI in a 2 weekly schedule | Drug: AZD8931<br>* 160 mg AZD8931 tablets, twice daily on days 1 - 4 of each 2-weekly cycle<br>Drug: Irinotecan<br>* 180 mg/m2 (IV infusion) of Irinotecan on day 1 of each 2-weekly cycle - can be given simultaneously with Folinic acid.<br>Drug: Folinic Acid<br>* 350 mg (IV infusion) of Folinic acid on day 1 of each 2-weekly cycle - can be given simultaneously with Irinotecan.<br>Drug: Fluorouracil<br>* 400 mg/m2 (IV bolus) of Fluorouracil on day 1 of each 2-weekly cycle, to be given after completion of Irinotecan and Folinic acid.<br>Drug: Fluorouracil<br>* 2400 mg/m2 (IV) continuous infusion of Fluorouracil given over 46 hours - infusion to start after 5FU bolus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response | Best overall response will be assessed according to RECIST v1.1. | From registration to date of documented best response, assessed up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of AZD8931 plus FOLFIRI | Percentage change in tumour size will be considered the best response only if a second assessment has been carried out which confirms SD at least four weeks after trial entry. Assessment will be determined using CT scans performed at baseline, 12 weeks after start of chemotherapy, then every 3 months until disease progression up to 3 years from registration/ randomisation | Baseline to 12 weeks post treatment start | 
| Progression Free Survival | Progression-free survival time will be calculated from the date of trial entry to the date of documented progression, or death from any cause. In cases where progression is suspected and subsequently confirmed by scans, the date of documented suspected progression will be used. | From date of randomisation to date of documented disease progression or death from any cause, whichever comes first, assessed up to 3 years from date of registration/ randomisation | 
| Overall Survival | Overall survival time will be calculated from the date of trial entry to the date of death from any cause or end of trial follow-up. | From date of registration/ randomisation until date of death or date of last follow-up assessment (up to 3 years from date of registration/ randomisation) | 
| Occurrence and Severity of Adverse Events | Will include all grade 1-5 adverse events | From date of registration/ randomisation until 30 days after completion of trial treatment (AZD8931 and FOLFIRI) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, Metastatic Colorectal cancer, Recurrent Colorectal cancer, FOLFIRI, AZD8931, Chemotherapy, EGFR