Roche trials database

Protocol number:

WO20024

Title of Study:

Phase Ib, open-label, multi-center study of the combination of pertuzumab and erlotinib in patients with locally advanced or metastatic (stage IIIb/IV) NSCLC after failure of at least one prior chemotherapy regimen.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

pertuzumab

Generic name:

pertuzumab

Therapeutic area:

• Non-Small Cell Lung Cancer

Clinical study summary:

This was an open-label, multi-center study (with sequential-cohort design) to evaluate the safety and tolerability and preliminary activity of the combination of a fixed dose of pertuzumab with two different doses of erlotinib in patients with locally advanced or metastatic (stage IIIb/IV) non-small cell lung cancer (NSCLC) who have failed at least one prior chemotherapy regimen.

Study center(s):

3 centers in Belgium, Spain, United Kingdom

Phase of development:

I

Objectives:

The primary objective was to determine the Maximum Tolerated Dose (MTD) and the dose-limiting toxicities (DLTs) of the combination of pertuzumab and erlotinib.

The secondary objectives were as follows: to assess the safety and tolerability of the combination of pertuzumab and erlotinib (including the effects on left ventricular function); to make a preliminary assessment of the activity of this regimen as demonstrated by objective response rate in patients with NSCLC; to evaluate any pharmacokinetic interaction between pertuzumab and erlotinib; to assess the expression and activation pattern of the HER family of receptors, their ligands and downstream signaling components in paraffin-embedded tissue and blood serum.

Methodology:

Following determination of eligibility, patients were treated in a sequential manner according to the treatment cycle plan. Erlotinib was administered orally, once daily starting on day -8 of cycle 1. Erlotinib was administered as single agent for the first 8 days (day -8 to day -1). Pertuzumab was administered as iv infusion on day 1 of cycle 1, and every 3 weeks thereafter. Treatment continued until disease progression, unacceptable toxicity or the patient’s wish to withdraw from the trial.

Adverse events and abnormal laboratory results were assessed according to the CTCAE version 3.0 grading system. Cardiotoxicity, was assessed measuring LVEF by ECHO or MUGA. LVEF and ECOG were assessed up to 42 days (to allow for potential delays) after the last dose of study drug (either pertuzumab or erlotinib, whichever was later).Tumor response was assessed according to RECIST. Blood samples were collected to evaluate the pharmacokinetics of pertuzumab and erlotinib.

Number of patients (planned/analyzed):

15 patients treated

Diagnosis and main criteria for inclusion:

Adult patients, >/= 18 years of age, with locally advanced or metastatic (stage IIIb/IV) non-small cell lung cancer who have failed at least one prior chemotherapy regimen

Test product, dose and mode of administration or test procedure:

Pertuzumab 840mg loading dose followed by 420mg every 3 weeks iv, plus

Erlotinib 100mg or 150mg orally, once daily

Duration of treatment:

until disease progression, unacceptable toxicity or patient's withdrawal

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Safety

Primary: Dose-Limiting Toxicity (DLT) was assessed during the first treatment cycle, and was defined, per the final protocol version B, as:

• Any non-hematological toxicity ≥ CTCAE Grade 3 except for fever, chills, flu-like symptoms and skin and/or epithelial toxicities, consistent with those observed in association with erlotinib single-agent therapy, unless they did not respond to treatment or to dose reduction or interruption. Grade 4 skin and/or epithelial toxicities were considered to be DLT.
• Grade 4 neutropenia of > 7 days.
• Febrile neutropenia - Grade 4 thrombocytopenia or any thrombocytopenia requiring platelet transfusion.
• Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds.

Secondary: Clinical adverse events and laboratory abnormalities were collected and graded according to CTCAE version 3.0. Cardiac monitoring (ECHO/MUGA) was performed at scheduled time points during the study.

Efficacy

Overall objective response rate was estimated, using RECIST criteria for patients with measurable lesions.

Pharmacokinetics:

Pharmacokinetic assessments were performed for pertuzumab and for erlotinib (OSI-774) and its metabolite (OSI-420).

Statistical methods:

No formal hypothesis testing was planned.

Summary (efficacy, safety, other results):

Safety

No DLTs, as per protocol B, were observed. Combination treatment was generally well tolerated and most toxicities had a CTC grade of 1 or 2. Overall, there was an increase in diarrhea and rash associated with the combination of erlotinib and pertuzumab compared to that which one would expect if either drug were given separately. These adverse events were manageable, either by support medications or by dose reduction of the erlotinib, and the combination of full dose erlotinib (150 mg orally per day) and full dose pertuzumab was tolerable. Five serious adverse events were reported in four patients, only one of which (diarrhea) was regarded as possibly related to the study drug. There were no patients with a decline in LVEF of >/= 10% points to an absolute value < 50%, however, three cardiac-related adverse events were reported, one patient reporting NYHA classification II for the event, myocardial infarction (considered unrelated to study treatment).

Overall, the AEs reported in this study were consistent with AEs which one would anticipate in this patient population receiving pertuzumab and erlotinib.

Pharmacokinetics

Pertuzumab - The pharmacokinetic data and resulting concentration-time curves from this study were comparable with data from the same dosing regimen in study BO17021 (pertuzumab given in combination with docetaxel). Pertuzumab mean exposures were slightly higher in the current study, while clearance, volume of distribution and terminal half -life were comparable to those from BO17201.

Erlotinib - The variability of the data in this study appears to be high but they were comparable with population PK data generated in previous studies in NSCLC patients. Taking into account the small N and the variability of the data, particularly for cycle 2 the data in this study suggest that there is no significant effect of pertuzumab on the PK of erlotinib.

Efficacy

Overall, the best response rate for all fifteen treated patients was after two treatment cycles, at which time five of the patients had stable disease and three showed a partial response. In addition, at the end of cycle 4, three patients showed a partial response and two had stable disease. One patient had stable disease until the end of the 12th cycle but progressed by the end of cycle 14. Another patient showed partial response until the end of cycle 14 but progressed at the end of cycle 16. The overall median progression-free survival (PFS) was 9.30 weeks with a range of 0 to 48 weeks.

Conclusions:

• No dose-limiting toxicities, as per protocol B, were observed.
• Combination treatment was generally well-tolerated and most toxicities were CTC grade 1 or 2.
• Although there was an overall increase in diarrhea and rash associated with the combination of erlotinib and pertuzumab, these adverse events were manageable.
• In future Phase II studies, the dose recommendation would be for patients to commence therapy with a full dose of pertuzumab (840mg IV loading dose with 420mg IV every 3 weeks) and a full dose of erlotinib (150mg orally per day) and if there were substantial diarrhea or rash, the dose of erlotinib is to be reduced to 100mg orally per day and if necessary a further reduction to 50mg orally per day.
• Three of the fifteen treated patients showed a partial response and two had stable disease over a period of at least four treatment cycles.
• The numbers are small, but the overall response rate (20.0%) is encouraging and further investigation of this combination is warranted.
• The PK of pertuzumab, when administered in combination with erlotinib, was comparable to that observed in previous studies. Similarly, the presence of pertuzumab did not appear to affect the PK of erlotinib in this study.

Date of report:

01.06.2009

Click here for the protocol registry listing of this trial.