Patient case: 56-year-old female with breast cancer; genetic feature: ERBB2

Clinical trial: Phase I/II Trial of Antagonism of HER in GI Cancer

Summary: Recruitment to phase I of the PANTHER trial is complete.
  In phase II, the combination of AZD8931 and FOLFIRI will be compared to FOLFIRI alone, to determine the efficacy of the treatment.

Detailed description: PANTHER is a registered phase I/randomised phase II trial in patients with recurrent or metastatic colorectal cancer.
  The phase II part of the study will be a randomised, controlled, 2 arm trial. Patients will be randomised to: receive AZD8931 (an EGFR/ERBB inhibitor) in combination with FOLinic acid, Fluorouracil and IRInotecan (FOLFIRI), or FOLFIR alone (control group).
  Treatment will be given in two-weekly cycles. Phase II's primary objective is to evaluate the efficacy of AZD8931 plus FOLFIRI alongside FOLFIRI alone using the percentage change in tumour size from baseline at 12 weeks after start of treatment.

Eligibility: Inclusion Criteria:
  1. Histopathological/cytological diagnosis of non-resectable, recurrent or metastatic colorectal cancer
  2. Tumour with wild-type RAS
  3. Measurable disease evaluated by RECIST criteria v1.1
  4. WHO performance status 0 or 1
  5. Age ≥ 16
  6. Estimated life expectancy > 3 months
  7. Adequate haematological function:
  -  Haemoglobin ≥100 g/L
  -  Absolute neutrophil count ≥1.5 x 10^9/L
  -  Platelet count ≥100 x 10^9/L
  8. Adequate liver function:
  -  Total bilirubin ≤1.5 x upper limit of normal (ULN)
  -  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
  9. Adequate renal function:
  -  Serum creatinine ≤1.5 x ULN
  -  Calculated creatinine clearance ≥30 mL/min
  10. Adequate biliary drainage (patients with stents are eligible)
  11. Adequate venous access for collection of exploratory biological samples
  12. 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
  13. Must be able to swallow AZD8931 tablets
  14. Capable of giving written informed consent
  15. 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:
  1. Patients undergoing treatment with curative intent
  2. Any prior treatment with agents targeting the ERBB pathway
  3. Treatment with experimental drugs within 30 days or 5 half-lives of first dose of AZD8931
  4. Previous chemotherapy for metastatic disease
  5. Prior treatment with anthracyclines or mitoxantrone
  6. 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)
  7. History of prior malignancy that will interfere with the response evaluation (exceptions listed in protocol)
  8. Evidence of severe/uncontrolled systemic diseases or laboratory finding that makes it undesirable for the patient to participate in the trial
  9. Evidence of active uncontrolled infection
  10. Patients with clinically significant ascites and/or effusions
  11. Regular use of anti-diarrhoeal
  12. Pregnant or lactating women
  13. Cardiac conditions (as detailed in the trial protocol)
  14. Any psychiatric or other disorder (e.g. brain metastases) likely to impact the ability to give informed consent
  15. Eye conditions (as detailed in the trial protocol)
  16. Patients with chronic skin conditions e.g. acne rosacea, psoriasis, severe atopic eczema
  17. 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
  18. History or repeated unexplained episodes of syncope/dizziness
  19. Known hypersensitivity to AZD8931, its excipients, or drugs in its class
  20. 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
  21. Patients with hereditary fructose intolerance

Relevance to patient case: not relevant