| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| In part 1 of the study: any solid tumor with the exemption of sarcoma. In part 2: any solid tumor or hematological malignancy |
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| E.1.1.1 | Medical condition in easily understood language |
| In part 1 of the study: any solid tumor with the exemption of sarcoma. In part 2: any solid tumor or hematological malignancy |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
• To assess the anti-tumor activity of the genomics guided therapy.
• To describe and assess the clinical feasibility, including safety, of therapy selection based on genomic profiling of fresh tumor tissue. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the anti-tumor activity of study drug with that of the drug treatment preceding that in this trial.
• To describe the safety profile of commercially available anti-cancer drugs used for off-label treatment of patients with an advanced solid tumor (part 1 and 2) or hematological malignancy (part 2) that harbors a predictive biomarker and starts therapy in accordance with this marker.
• To compare two different types of platforms for genomic profiling, bioinformatics analysis and clinical decision-making: clinical assays in routine use at the participating centers versus the Foundation Medicine platform; F1CDx (Part 1).
• To compare outcome of patients starting treatment in accordance with a genomic marker with patients included in the trial that do not start such treatment due to absence of appropriate marker. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria:
1. Adult (age >18 years)
2. Patients with histologically-proven, locally advanced or metastatic solid tumor (part 1; hematological malignancies also eligible in part 2) progressive while on last line established therapy considered available for the patient. For re-recruitment (part 2, defined by section 7.8 of the protocol) patients must be progressive while on trial defined treatment or off-protocol treatment.
3. Fresh tumor sampling by biopsy must be possible, except for patients with CNS malignancy who can be included based on molecular analysis of archived tumor material.
4. ECOG performance status 0-2.
5. Patients must have acceptable organ function as defined below. However, specific inclusion/exclusion criteria specified in main protocol will take precedence:
a. Absolute neutrophil count ≥ 1.5 x 10^9/L
b. Hemoglobin > 90 g/L
c. Platelets > 75 x 10^9/L
d. Total bilirubin < 2 x ULN
e. ASAT (SGOT) and ALAT (SGPT) < 2.5 x institutional ULN (or < 5 x ULN in patients with known hepatic metastases)
f. Serum creatinine ≤ 1.5 ULN or calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2
6. Patients must have objectively measurable disease (by physical or radiographic examination).
7. Ability to understand and the willingness to sign a written informed consent document.
8. For orally administered drugs, the patient must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome.
9. Negative pregnancy test in women of childbearing potential (premenopausal or <12 months of amenorrhea post-menopause and who have not undergone surgical sterilization). Women of childbearing potential must use highly effective method of contraception, i.e. combined hormonal contraception, or progestogen-only hormonal contraception, or intrauterine device, or intrauterine hormone-releasing system, or bilateral tubal occlusion, or vasectomized partner, or sexual abstinence for the duration of participation in the study, and four months following completion of study therapy.
10. Selected tumor types might have disease-specific inclusion criteria as defined by disease-specific study appendix (section 17.6 of the protocol). |
|
| E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study:
1. Ongoing treatment-related toxicity > grade 2.
2. Patients receiving any other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) except for medications that are prescribed for supportive care but may potentially have an anti-cancer effect (e.g., megestrol acetate, bisphosphonates, somatostatin analogues and prednisone, or equivalent). These medications must have been started ≥ 1 week prior to the screening visit on this study. Radiotherapy to non-target lesions is allowed.
3. Patients pregnant or nursing.
4. Patients of childbearing potential and sexually active and not willing to use highly effective contraceptive.
5. Patients with known active progressive CNS metastases. Patients with previously treated CNS metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to inclusion. All patients with previously treated CNS metastases must be stable for at least 1 month after completion of treatment and off steroid treatment prior to inclusion.
6. Some concomitant diseases qualified for exclusion as detailed in main protocol.
7. Other serious underlying medical conditions, which, in the Investigator’s judgment, could impair the ability of the patient to participate in the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Efficacy: number of patients in each cohort with objective tumor response, generally as defined by RECIST version 1.1 (or, as applicable, tumor type specific) criteria. Tumor response need to be confirmed.
• Feasibility and safety of comprehensive genomic testing of fresh tumor tissue for treatment decision, defined as the proportion of patients included with actionable genomic analysis within 4 weeks from inclusion and procedure related adverse events National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 < grade 3. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints:
• Additional measurements of treatment efficacy: time to and duration of tumor response (ORR) and stable disease, progression free survival (PFS), overall survival (OS) and progression free survival (PFS) on study drug compared with that on the treatment preceding study drug treatment.
• Incidence and severity of study drug related adverse events (AEs) and serious adverse events (SAEs) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
• Safety of core needle biopsy in advanced cancer scored according to NCI Common Terminology Criteria for Adverse Events 4.03 as grade 3-4 adverse event related to the procedure.
• Actionable target concordance between genomic analysis results from the Foundation Medicine platform F1CDx with that from the similar local analysis.
• Overall survival of patients starting treatment in accordance with 1 of the 4 groups of genomic markers compared with patients included in the trial but that do not start such treatment due to lack of appropriate marker.
Exploratory endpoints:
• Findings suggestive of tumor properties as indicated in analyses of biomaterial collected before and during the trial and overlap of actionable biomarkers between archived tissue and tumor biopsy at baseline.
• Translational research analyses on biomaterial collected and accessible within the trial addressing, e.g. the evolution of tumor properties by comparing fresh with archived tumor tissue, the metastatic process, tumor biology as well as drug activity and resistance ex vivo and in patient-derived xenograft mouse models.
• Overlap of actionable predictive biomarkers in tumor tissue and liquid biopsies. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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