Phase I/II Trial of Antagonism of HER in GI Cancer (PANTHER)

• ClinicalTrials.gov Identifier: NCT01862003
• Recruitment Status: Completed
• First Posted: May 24, 2013
• Last Update Posted: August 19, 2019
• Sponsor: University College, London
• Collaborators: Cancer Research UK; AstraZeneca; National Institute for Health Research, United Kingdom
• Information provided by (Responsible Party): University College, London

Tracking Information

• First Submitted Date: May 7, 2013
• First Posted Date: May 24, 2013
• Last Update Posted Date: August 19, 2019
• Study Start Date: May 2014
• Actual Primary Completion Date: August 2, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2017)

Best overall response [ Time Frame: From registration to date of documented best response, assessed up to 36 months ]

Best overall response will be assessed according to RECIST v1.1.

Original Primary Outcome Measures (submitted: May 21, 2013)

Occurrence of Dose Limiting Toxicity [ Time Frame: From start of cycle 1 to end of cycle 1 (each cycle = 2 weeks) ]

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.

Current Secondary Outcome Measures (submitted: September 8, 2017)

• To evaluate the efficacy of AZD8931 plus FOLFIRI [ Time Frame: Baseline to 12 weeks post treatment start ]
  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
• Progression Free Survival [ Time Frame: 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 ]
  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.
• Overall Survival [ Time Frame: 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) ]
  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.
• Occurrence and Severity of Adverse Events [ Time Frame: From date of registration/ randomisation until 30 days after completion of trial treatment (AZD8931 and FOLFIRI) ]
  Will include all grade 1-5 adverse events

Original Secondary Outcome Measures (submitted: May 21, 2013)

• Measurement of Pharmacokinetic parameters (AUC, Cmax, t1/2) of AZD8931, Irinotecan and metabolite concentrations [ Time Frame: PK parameters taken - pre-dose, 1.5, 2 or 2.5, 4, 8 & 10 hrs post AZD8931 dose or after starting irinotecan - measurements taken pre-FOLFIRI, cycle 1 day 1 & cycle 2 day 1; pre-AZD8931 dose on cycle 1 day 2 & cycle 2 day 2 ]
  PK analysis of plasma AZD8931, irinotecan and metabolite concentrations. Blood samples (plasma) will be taken on the following days: Pre-treatment (before any trial related treatment), AZD8931 alone Day 1, Cycle 1 Day 1, Cycle 1 Day 2, Cycle 2 Day 1, Cycle 2 Day 2.
• Change in tumour size from baseline at 12 weeks using RECIST v1.1 [ Time Frame: Baseline CT scan compared to CT scan taken 12 weeks after start of combination chemotherapy ]
  A sum of the diameters for all target lesions will be calculated according to RECIST v1.1. The difference between the baseline sum of diameters and the week 12 sum will be the change in tumour size at 12 weeks after the start of chemotherapy.
• Best overall response [ Time Frame: Determined using CT scans performed at baseline (registration), 12 weeks after start of chemotherapy, then every 3 months until disease progression up to 3 years from date of registration ]
  Best overall response will be assessed according to RECIST v1.1. Confirmation of complete or partial response is not required. Stable disease 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
• Progression Free Survival [ Time Frame: From date of registration to date of documented disease progression or death from any cause, whichever comes first, assessed up to 3 years from date of registration ]
  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.
• Overall Survival [ Time Frame: From date of registration until date of death or date of last follow-up assessment (up to 3 years from date of registration) ]
  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.
• Occurrence and Severity of Adverse Events [ Time Frame: From date of registration until 30 days after completion of trial treatment (AZD8931 and FOLFIRI) ]
  Will include all grade 1-5 adverse events

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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

Brief Summary

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

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

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Colorectal Cancer
• Recurrent Colorectal Cancer

Intervention

• Drug: AZD8931
  160 mg AZD8931 tablets, twice daily on days 1 - 4 of each 2-weekly cycle
• Drug: Irinotecan
  180 mg/m2 (IV infusion) of Irinotecan on day 1 of each 2-weekly cycle - can be given simultaneously with Folinic acid.
• Drug: Folinic Acid
  350 mg (IV infusion) of Folinic acid on day 1 of each 2-weekly cycle - can be given simultaneously with Irinotecan.
• Drug: Fluorouracil
  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.
• Drug: Fluorouracil
  2400 mg/m2 (IV) continuous infusion of Fluorouracil given over 46 hours - infusion to start after 5FU bolus.

Study Arms

Experimental: Arm 1

AZD8931 160 mg bd, on days 1-4, + FOLFIRI in a 2 weekly schedule

Interventions:

• Drug: AZD8931
• Drug: Irinotecan
• Drug: Folinic Acid
• Drug: Fluorouracil
• Drug: Fluorouracil

• Publications *: Propper DJ, Gao F, Saunders MP, Sarker D, Hartley JA, Spanswick VJ, Lowe HL, Hackett LD, Ng TT, Barber PR, Weitsman GE, Pearce S, White L, Lopes A, Forsyth S, Hochhauser D. PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer. Br J Cancer. 2023 Jan;128(2):245-254. doi: 10.1038/s41416-022-02015-x. Epub 2022 Nov 9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 21, 2013): 24
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 2, 2019
• Actual Primary Completion Date: August 2, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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) (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

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 palliative chemotherapy
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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT01862003
• Other Study ID Numbers: UCL/12/0136
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University College, London
• Original Responsible Party: Same as current
• Current Study Sponsor: University College, London
• Original Study Sponsor: Same as current

Collaborators

• Cancer Research UK
• AstraZeneca
• National Institute for Health Research, United Kingdom

Investigators

• Principal Investigator: Daniel Hochhauser, BA, MBBS, MRCP, D.PHIL, FRCP; University College London (UCL) Cancer Institute

• PRS Account: University College, London
• Verification Date: August 2019