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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

Phase 1
18 Years
Not Enrolling
Metastatic Colorectal Cancer, Recurrent Colorectal Cancer

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Trial Information

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

PANTHER is a registered phase I/randomised phase II trial in patients with recurrent or
metastatic colorectal cancer. Patients are recruited to received AZD8931 (an EGFR/ERBB
inhibitor) in combination with FOLinic acid, Fluorouracil and IRInotecan (FOLFIRI). AZD8931
and FOLFIRI will be given in two-weekly cycles. The Phase I trial will aim to determine the
recommended Phase II dose of AZD8931 (either 20, 40, 80 or 160mg bd, on days 1-4 of each
2-weekly cycle) - the dose of AZD8931 that patients will receive will depend on the dose
under investigation at the time of registration.

The AZD8931 dose will be determined by the Modified Continual Reassessment Method (mCRM).
mCRM is a dose-toxicity model which describes the probability of a toxicity occurring at
each dose level, which is based on clinical judgment and any available toxicity data.

The recommended AZD8931 dose in combination with FOLFIRI, determined from the phase I trial,
will become one of the treatment groups in the randomised Phase II - the other treatment
group will be FOLFIRI alone (Control group).

Inclusion Criteria:

1. Histopathological/cytological diagnosis of non-resectable, recurrent or metastatic
colorectal cancer

2. Tumour with wild-type KRAS

3. Measurable disease evaluated by RECIST criteria v1.1

4. WHO performance status 0 or 1

5. Age ≥ 18

6. Estimated life expectancy > 3 months

7. Adequate haematological function:

- Haemoglobin ≥100 g/L

- WBC ≥3.0 x 10^9/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

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

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

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

21. Patients with hereditary fructose intolerance

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Occurrence of Dose Limiting Toxicity

Outcome Description:

Detailed adverse event monitoring will be conducted according to CTCAE v4.03. Dose Limiting Toxicity (DLT) is defined as any adverse event or laboratory abnormality detailed in the trial protocol, that is considered to be related to AZD8931 and commencing anytime during the DLT evaluation period (from start of cycle 1 to end of cycle 1). Adverse Events include: Skin, Gastrointestinal, Haematological, Clinical Chemistry, Cardiovascular.

Outcome Time Frame:

From start of cycle 1 to end of cycle 1 (each cycle = 2 weeks)

Safety Issue:


Principal Investigator

Daniel Hochhauser, BA, MBBS, MRCP, D.PHIL, FRCP

Investigator Role:

Principal Investigator

Investigator Affiliation:

University College London (UCL) Cancer Institute


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

August 2013

Completion Date:

August 2018

Related Keywords:

  • Metastatic Colorectal Cancer
  • Recurrent Colorectal Cancer
  • Colorectal cancer
  • Metastatic Colorectal cancer
  • Recurrent Colorectal cancer
  • AZD8931
  • Chemotherapy
  • EGFR
  • Colorectal Neoplasms