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

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

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