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A Phase I/II Trial of Pertuzumab in Combination With Cetuximab and Irinotecan in Previously Treated Metastatic Colorectal Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage III Colon Cancer, Stage III Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

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Trial Information

A Phase I/II Trial of Pertuzumab in Combination With Cetuximab and Irinotecan in Previously Treated Metastatic Colorectal Cancer


I. To determine the safety, tolerability, and recommended phase II dose of pertuzumab when
administered in combination with cetuximab in patients with cetuximab-refractory locally
advanced or metastatic colorectal cancer.

II. To evaluate the objective tumor response rate (RR) in patients treated with this


I. To evaluate the median progression-free survival (PFS) of patients treated with this

II. To evaluate the median overall survival (OS) of patients treated with this regimen.

III. To evaluate the RR, PFS, and OS in a subgroup of patients who are EGFR-positive by

IV. To explore the relationship between skin rash and the efficacy outcomes of RR, PFS, and
OS in these patients.

V. To explore the relationship between objective tumor response on positron emission
tomography (PET) scan after course two and the efficacy outcomes of RR, PFS, and OS in these

VI. To explore the relationship between a variety of laboratory correlates and the efficacy
outcomes of RR, PFS, and OS in these patients.

OUTLINE: This is a multicenter, phase I dose-escalation study of pertuzumab followed by a
phase II study.

PHASE I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive
cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15
in all subsequent courses.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive treatment as in phase I. Pertuzumab is administered at the
recommended phase II dose (determined in phase I). Previously collected tumor tissue samples
are analyzed for correlative studies. Samples are analyzed for KRAS mutations via polymerase
chain reaction and pyrosequencing; EGFR expression via immunohistochemistry and fluorescent
in situ hybridization (FISH); HER receptor and ligand gene expression; and circulating tumor
cells. Additional blood samples are collected periodically to isolate circulating tumor
cells and are analyzed via FISH analysis.

After completion of study treatment, patients are followed at 30 days and then periodically

Inclusion Criteria:

- Patients with a history of colorectal cancer (CRC) treated by surgical resection and
who develop radiological or clinical evidence of metastatic disease do not require
separate histological or cytological confirmation of metastatic disease unless 1 of
the following criteria are met:

- More than 5 years has elapsed between the primary surgery and the development of
metastatic disease

- The primary cancer was stage I

- Patients must have representative tumor specimens in paraffin blocks or at least 15
unstained slides with an associated pathology report obtained at any time prior to
study entry:

- Cytology specimens are not acceptable replacements

- Patients must have their tumor tissue screened for KRAS mutation status, and be found
to have a KRAS wild-type tumor:

- No KRAS-mutated tumor

- Locally advanced or metastatic disease

- Not curable by surgery or amenable to radiotherapy with curative intent

- Must have received an cetuximab-containing regimen for at least 6 weeks for treatment
of metastatic disease

- Documented progression of disease or intolerable toxicity during or within 3 months
of receiving this regimen

- Patients who have received an cetuximab-containing regimen as adjuvant therapy for
resected stage II or III CRC are eligible provided recurrent disease is documented <
6 months after completion of adjuvant treatment

- Must have received >= 1 prior chemotherapeutic regimen for treatment of metastatic
disease with any of the following:

- Cetuximab

- Must have resolution of any skin rash related to prior treatment with cetuximab

- No prior cetuximab which required a dose reduction for toxicity

- 5-fluorouracil or capecitabine

- Irinotecan hydrochloride or oxaliplatin

- Measurable disease by CT scan or physical exam

- ECOG performance status (PS) 0-1 (Karnofsky PS 70-100%)

- Life expectancy > 12 weeks

- Absolute neutrophil count >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Leukocytes >= 3,000/mcL

- Hemoglobin >= 9 g/dL (transfusion, erythropoietin, or other approved hematopoietic
growth factors allowed)

- Total bilirubin =< 1.5 times upper limit of normal (ULN)

- AST and ALT =< 5 times ULN

- Creatinine normal OR Creatinine clearance >= 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception prior to and during study therapy

- Cardiac left ventricular ejection fraction >= 50% OR >= lower limit of normal

- No evidence of left ventricular wall motion abnormalities as measured by ECHO or MUGA

- None of the following cardiac conditions:

- Uncontrolled high blood pressure

- Unstable angina

- Symptomatic congestive heart failure

- Congestive heart failure, cardiac dysfunction, or cardiomyopathy requiring
medication treatment

- Myocardial infarction within the past 6 months

- Serious uncontrolled cardiac arrhythmia

- New York Heart Association class III or IV heart disease

- No active or uncontrolled infection

- No predisposing colonic or small bowel disorders in which the symptoms are
uncontrolled as indicated by baseline pattern of > 3 loose stools/day (in patients
without a colostomy or ileostomy)

- Patients with a colostomy or ileostomy may be eligible at investigator discretion

- No psychiatric illness/social situation that would limit compliance with study

- No other prior or concurrent malignancy, except for adequately treated basal cell or
squamous cell skin cancer, in situ carcinoma of the cervix, lobular carcinoma in situ
in one breast, or other cancer from which the patient has been disease-free for at
least 5 years

- No other medical or psychiatric disease, metabolic dysfunction, physical examination
finding, or clinical laboratory finding giving reasonable suspicion of a disease or
condition that contraindicates the use of an investigational drug or that may affect
the interpretation of the study results or render the patient at high risk for
treatment complications

- No history of allergic reactions, hypersensitivity, or intolerance to cetuximab,
and/or compounds of similar chemical or biologic composition to pertuzumab or
cetuximab (i.e., other monoclonal antibodies such as bevacizumab) that led to
discontinuation of the drug

- Patients able to tolerate subsequent infusions after a reaction are eligible

- At least 4 weeks since prior major surgery (e.g., laparotomy) and recovered
(Insertion of a vascular access device is not considered major or minor surgery)

- At least 2 weeks since prior minor surgery and recovered (Insertion of a vascular
access device is not considered major or minor surgery)

- At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative

- At least 4 weeks since prior bevacizumab

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
and recovered

- No prior agents directed against EGFR and/or HER2

- No more than one prior treatment regimen for metastatic disease; Prior chemotherapy
in the adjuvant setting following resection of stage II or III disease allowed
provided the regimen did not contain irinotecan hydrochloride and/or an agent
directed against EGFR and/or HER2

- No prior doxorubicin or liposomal doxorubicin at doses > 360 mg/m^2; epirubicin at
doses > 720 mg/m^2; mitoxantrone at doses > 120 mg/m^2; or idarubicin at doses > 90

- No prior radiotherapy to > 15% of the bone marrow

- No prior standard adjuvant chemoradiotherapy for rectal cancer

- No phenytoin, phenobarbital, carbamazepine, or any other enzyme-inducing
anti-convulsant drugs (EIACDs) for at least 7 days before, during, and for 7 days
after the final dose of irinotecan hydrochloride

- Concurrent gabapentin or other non-EIACDs are allowed

- No St. John's wort for at least 14 days before, during, and for 7 days after the
final dose of irinotecan hydrochloride

- No concurrent corticosteroids, except for stable doses of prednisone (< 20 mg/day or
equivalent), topical or inhaled corticosteroids, or corticosteroids for reasons
unrelated to treatment of colorectal cancer

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) for any of the following

- To avoid dose reductions or delays

- Prophylactic treatment

- Treatment of febrile neutropenia

- No other concurrent HER family-targeted therapy

- No concurrent rifampin

- No concurrent herbal remedies unless initiated prior to study entry

- No other concurrent investigational agents

- No other concurrent anticancer therapy, including cytotoxic chemotherapy,
radiotherapy, immunotherapy, hormonal therapy, or biological anticancer therapy

- Histologically or cytologically confirmed adenocarcinoma of the colon or rectum

- Site of the primary lesion must be or have been confirmed endoscopically,
radiologically, or surgically to be or have been in the large bowel

- No known brain metastases

- No concurrent fluconazole

Type of Study:


Study Design:

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

Outcome Measure:

Recommended phase II dose of pertuzumab when administered in combination with cetuximab (Phase I)

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Kimmie Ng

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

October 2007

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Colon
  • Adenocarcinoma of the Rectum
  • Recurrent Colon Cancer
  • Recurrent Rectal Cancer
  • Stage III Colon Cancer
  • Stage III Rectal Cancer
  • Stage IV Colon Cancer
  • Stage IV Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Colorectal Neoplasms



Dana-Farber Cancer Institute Boston, Massachusetts  02115