E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer expressing wild type (wt) KRAS and refractory to irinotecan- and oxaliplatin-containing regimens, or refractory to oxaliplatin-containing regimens. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part 1: To determine if acquired resistance to panitumumab therapy in subjects with KRAS wild-type mCRC correlates with emergence of mutant KRAS tumors. (Acquired resistance is defined as disease progression on panitumumab and irinotecan that occurs after a period of disease response or stable disease on treatment with this regimen is observed and radiographicallyconfirmed.) Part 2: To determine if inhibition of the IGF-1R pathway with AMG 479 can overcome resistance to panitumumab therapy, as demonstrated by the objective response rate (ORR) to panitumumab and AMG 479 following disease progression on panitumumab and irinotecan. |
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E.2.2 | Secondary objectives of the trial |
Part 1: To determine ORR and other measures of efficacy (ie, TTR, DOR, PFS, OS) to panitumumab plus irinotecan To evaluate the safety of panitumumab and irinotecan Part 2: To determine measures of efficacy (ie, TTR, DOR, PFS, OS) of panitumumab plus AMG 479 To evaluate the safety of panitumumab and AMG 479 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum Subjects with wild-type KRAS tumor status confirmed by central laboratory assessment Radiographic evidence of disease progression while on or ≤ 6 months after 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 CT or MRI or ≥ 10 mm by spiral CT per modified RECIST. 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 (metastatic lesion or unresected primary tumor) that is amenable to core needle biopsy, as determined by the clinician who will perform the biopsy Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Male or female ≥ 18 years of age at the time of informed consent Willing to undergo two core biopsy procedures of tumors (metastasis or unresected primary) |
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E.4 | Principal exclusion criteria |
History of prior or concurrent central nervous system (CNS) metastases Prior treatment with anti-EGFR antibodies (eg, panitumumab, cetuximab) or EGFR small molecule inhibitors (eg, erlotinib, gefitinib) Prior treatment with monoclonal antibodies directed against IGF-1R Use of systemic chemotherapy and radiotherapy ≤ 21 days before enrollment Use of any antibody therapy (eg, bevacizumab) ≤ 42 days before enrollment Use of anti-tumor therapies including prior experimental agents or approved anti-tumor small molecules ≤ 30 days before enrollment Known 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 computerized tomography (CT) scan Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection Any co-morbid disease or condition that could increase the risk of toxicity (eg, significant ascites, significant pleural effusion) Any uncontrolled concurrent illness (eg, infection, bleeding diathesis) or history of any medical condition that may interfere with the interpretation of the study results Major surgical procedure ≤ 28 days before enrollment or minor surgical procedure ≤ 14 days before enrollment. Subjects must have recovered from surgery related toxicities. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Emergence of Mutant KRAS: KRAS mutation status changed from wild-type at baseline to mutant at the time of the second biopsy following the radiographic evidence of acquired resistance to panitumumab plus irinotecan (Part 1). Objective Response Rate (ORR): Confirmed complete or partial response (per modified RECIST) to panitumumab and AMG 479 (Part 2) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.3.1 | Comparator description |
- same IMP used at different dosage |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study for each subject is defined as the date the subject withdraws consent from the study, completes the final long-term follow-up visit, or death. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |