Clinical trial NCT00891930: Study to Evaluate Mechanisms of Acquired Resistance to Panitumumab
Official title: Phase 2 Study of Panitumumab Plus Irinotecan Followed by Panitumumab Plus AMG 479 in Subjects With Metastatic Colorectal Carcinoma Expressing Wild Type KRAS and Refractory to Oxaliplatin-or Irinotecan- and Oxaliplatin-containing Regimens to Evaluate Mechanisms of Acquired Resistance to Panitumumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: wild-type KRAS
panitumumab
biomarker
mechanisms of acquired resistance
metastatic colorectal cancer
Lead sponsor: NantBioScience, Inc.
Sponsor class: INDUSTRY
First posted: 2009-05-01
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is designed to evaluate the mechanism(s) of resistance to the anti-epidermal growth factor receptor (EGFR) antibody panitumumab given in combination with irinotecan in metastatic colorectal carcinoma (mCRC) patients with wild-type Kirsten rat sarcoma-2 virus oncogene (KRAS) tumor status at the time of initial diagnosis.

Detailed description: In Part 1, all participants will undergo a baseline tumor biopsy and will receive panitumumab with irinotecan. Participants who respond or have stable disease will continue to receive treatment until radiographically-confirmed disease progression. These participants will then undergo a second tumor biopsy and blood sampling and then proceed to Part 2 of the study. Participants with radiographically confirmed disease progression at the time of the first tumor measurement will undergo blood sampling and proceed directly to Part 2.

In Part 2, participants will receive panitumumab with ganitumab. In both parts of the study, panitumumab and irinotecan (Part 1) and panitumumab and ganitumab (Part 2) will be administered every 2 weeks until disease progression, intolerability, withdrawal of consent, death, or unless otherwise indicated by the study team.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum;
* Subjects with wild-type KRAS tumor status confirmed by an Amgen approved central laboratory assessment or an experienced local laboratory assessment of archival tumor tissue (preferably from the primary tumor);
* Radiographic evidence of disease progression while on or ≤ 6 months after completion of treatment with irinotecan- and oxaliplatin- or oxaliplatin-based chemotherapy for mCRC;
* Radiographic measurement of tumor burden done within 28 days prior to Day 1 (start of treatment with investigational product);
* At least 1 uni-dimensionally measurable lesion ≥ 20 mm using conventional computed tomography (CT) or magnetic resonance imaging (MRI) or ≥ 10 mm by spiral CT scan per modified RECIST v1.0. Lesion must not be chosen from a previously irradiated field, unless there has been documented disease progression in that field after irradiation and prior to enrollment. All sites of disease must be evaluated;
* At least 1 tumor (preferably a metastasis or unresected primary tumour) that is amenable to core biopsy, as determined by the clinician who will perform the biopsy;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
* A life expectancy estimate of ≥ 3 months;
* Willing to undergo two serial core biopsy procedures of tumors (metastasis or unresected primary);
* other criteria may apply

Exclusion Criteria:

* History of other primary cancer, unless:

  * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician,
* Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease,

  * Adequately treated cervical carcinoma in situ without evidence of disease,
  * Prostatic intraepithelial neoplasia without evidence of prostate cancer;
* History of prior or concurrent central nervous system (CNS) metastases;
* Prior treatment with anti-EGFR (eg, panitumumab, cetuximab or small molecule inhibitors (eg, erlotinib, gefitinib);
* Prior treatment with monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) or small molecule inhibitors directed against IGF-1R;
* Use of systemic chemotherapy or radiotherapy ≤ 21 days before enrollment. Subjects must have recovered from acute toxicities related to radiotherapy;
* Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrolment;
* Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small molecules ≤ 30 days before enrolment;
* Known allergy or hypersensitivity to any component of panitumumab, irinotecan, or AMG 479;
* Known uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphisms predisposing to increased irinotecan toxicity;
* History of irinotecan intolerance that may interfere with planned treatment;
* History of interstitial lung disease (eg, pneumonitis, pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan;
* Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment;
* Active inflammatory bowel disease or other active bowel disease causing chronic diarrhea (defined as ≥ grade 2 per Common Terminology Criteria for Adverse Events (CTCAE) version 3.0);
* Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection;
* Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days before enrollment. Subjects must have recovered from surgery related toxicities. Core biopsy, central venous catheter placement, fine needle aspiration, thoracentesis, or paracentesis is not considered a major or minor surgical procedure; - Other investigational procedures or drugs (ie, participation in another clinical study) ≤ 30 days before enrolment;
* other criteria may apply

Primary outcomes:
measure: PFS Hazard Ratio
timeFrame: From baseline up to 152 weeks (from baseline to the time of the second biopsy prior to entering part 2) .
measure: Objective Response Rate in Part 2
timeFrame: From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks)
Secondary outcomes:
measure: Objective Response Rate for Part 1
timeFrame: from first dose of investigational product up to 152 weeks
measure: Progression-Free Survival for Part 1
timeFrame: from first dose of investigational product up to 152 weeks
measure: Progression-Free Survival for Part 2
timeFrame: 119 weeks from the start of part 2, up to a maximum duration of 152 week
measure: Overall Survival for Part 1
timeFrame: from first dose of investigational product up to 152 weeks
measure: Overall Survival for Part 2
timeFrame: from the start of Part 2 up to 119 weeks
measure: Time to Response for Part 1
timeFrame: from first dose of investigational product up to 152 weeks
measure: Duration of Response for Part 1
timeFrame: from first dose of investigational product up to 152 weeks
measure: Part 2 Time to Response and Duration of Response
timeFrame: From time of randomization until confirmed complete response or partial response (part 2: up to 119 weeks)
Other outcomes:
Locations:
Study officials:
References:
citation: Siena S, Sartore-Bianchi A, Garcia-Carbonero R, Karthaus M, Smith D, Tabernero J, Van Cutsem E, Guan X, Boedigheimer M, Ang A, Twomey B, Bach BA, Jung AS, Bardelli A. Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer. Ann Oncol. 2018 Jan 1;29(1):119-126. doi: 10.1093/annonc/mdx504.