Clinical Trials /

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

NCT01862003

Description:

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

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Phase I/II Trial of Antagonism of HER in GI <span class="go-doc-concept go-doc-disease">Cancer</span>

Title

  • Brief Title: Phase I/II Trial of Antagonism of HER in GI Cancer
  • Official Title: 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
  • Clinical Trial IDs

    NCT ID: NCT01862003

    ORG ID: UCL/12/0136

    Trial Conditions

    Metastatic Colorectal Cancer

    Recurrent Colorectal Cancer

    Trial Interventions

    Drug Synonyms Arms
    AZD8931 AZD8931 + FOLFIRI
    Irinotecan AZD8931 + FOLFIRI
    Folinic Acid AZD8931 + FOLFIRI
    Fluorouracil AZD8931 + FOLFIRI
    Fluorouracil AZD8931 + FOLFIRI

    Trial Purpose

    In phase I, the aim of the study is to determine the recommended phase II dose of AZD8931 in
    combination with standard chemotherapy, FOLFIRI, by assessing the safety and tolerability of
    the combination treatment.

    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. 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).

    Trial Arms

    Name Type Description Interventions
    AZD8931 + FOLFIRI Experimental AZD8931 (20, 40, 80 or 160 mg bd on days 1 - 4) in combination with FOLFIRI starting on day 1 of every 2-weekly cycle: Irinotecan 180 mg/m2 IV infusion, Folinic acid 350 mg IV infusion, Fluorouracil 400 mg/m2 IV bolus, Fluorouracil 2400 mg/m2 IV continuous infusion over 46 hours. AZD8931, Irinotecan, Folinic Acid, Fluorouracil, Fluorouracil

    Eligibility Criteria

    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
    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Occurrence of Dose Limiting Toxicity

    Secondary Outcome Measures

    Measurement of Pharmacokinetic parameters (AUC, Cmax, t1/2) of AZD8931, Irinotecan and metabolite concentrations

    Change in tumour size from baseline at 12 weeks using RECIST v1.1

    Best overall response

    Progression Free Survival

    Overall Survival

    Occurrence and Severity of Adverse Events

    Trial Keywords

    Colorectal cancer

    Metastatic Colorectal cancer

    Recurrent Colorectal cancer

    FOLFIRI

    AZD8931

    Chemotherapy

    EGFR