E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with histological or cytological proof of advanced KRAS mutant and PIK3CA wildtype non small cell lung cancer (NSCLC) and colorectal cancer (CRC). In part B: for which first-line treatment failed. |
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E.1.1.1 | Medical condition in easily understood language |
Advanced colorectal, pancreatic or non small cell lung cancer with mutations in the KRAS gene and no mutations in the PIK3CA gene |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029520 |
E.1.2 | Term | Non-small cell lung cancer stage IIIA |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029518 |
E.1.2 | Term | Non-small cell lung cancer stage II |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029519 |
E.1.2 | Term | Non-small cell lung cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10010023 |
E.1.2 | Term | Colorectal neoplasms malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061451 |
E.1.2 | Term | Colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010030 |
E.1.2 | Term | Colorectal cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010034 |
E.1.2 | Term | Colorectal cancer stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010035 |
E.1.2 | Term | Colorectal cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010036 |
E.1.2 | Term | Colorectal carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052360 |
E.1.2 | Term | Colorectal adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 A: To determine the recommended phase 2 dose and schedule (RP2D) of the selumetinib/afatinib combination in patients with KRASm and PIK3CAwt NSCLC and CRC
Part B: To determine the progression free survival (PFS) of the selumetinib/afatinib combination compared to standard of care therapy in patients with KRASm and PIK3CAwt , NSCLC and CRC
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E.2.2 | Secondary objectives of the trial |
To characterize the safety and tolerability of afatinib in combination with selumetinib, as assessed by the incidence and severity of adverse events
To determine the anti-tumor activity of afatinib in combination with selumetinib, as measured by overall response rate, duration of response, time to response and overall survival (Part B) To determine the pharmacokinetic profile of afatinib and selumetinib in this combination
Exploratory objectives
• To explore determinants (gene alteration/expression) and mode of response to the selumetinib-/afatinib combination, as measured by baseline and on-therapy molecular status (mutation/amplification/expression) in tumor tissue of potential predictive and indicative markers of tumor response
• To explore the potential mechanism of resistance to the selumetinib-/afatinib combination, as measured by gene alterations/expression profiles (e.g. baseline, relapse) in tumor tissue upon progression
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histological or cytological proof of advanced NSCLC or CRC. For PART B: treated with first line therapy for metastatic disease only.
2. Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (defined as absence of mutations in exon 9 and 20).
3. Age > 18 years.
4. Able and willing to give written informed consent.
5. WHO performance status of 0 or 1.
6. Able and willing to undergo blood sampling for PK and PD analysis.
7. Able and willing to undergo a tumor biopsy prior to start and upon progression of disease and in Part A after two weeks of therapy
8. All toxicities related to prior treatment should have resolved to CTCAE grade 1 or less (excluding alopecia)
9. Life expectancy > 3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
10. Measurable disease according to RECIST 1.1
11. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception throughout the treatment period, and for 4 months after the last dose of study treatment.
12. Adequate organ system function measured by laboratory values
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E.4 | Principal exclusion criteria |
1. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
2. History of another malignancy
Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies are eligible.
Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin.
3. Patients with pancreatic cancer treated with fluoropyrimidine containing therapy (PART B only).
4. Symptomatic or untreated leptomeningeal disease.
5. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 4 weeks) are allowed to enrol. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive anti-epileptic drugs or corticosteroids.
6. Patients previously treated with irinotecan, docetaxel, capecitabine (PART B only)
7. Patients previously treated with any drug known to interfere with EGFR, HER2, HER3, HER4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK.
8. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral afatinib and selumetinib (e.g., ulcerative diseases, uncontrolled nausea, malabsorption syndrome, small bowel resection).
9. History of interstitial lung disease or pneumonitis
10. Women who are pregnant or breast feeding.
11. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms).
12. Radio-, immuno- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed.
13. Patients who have undergone any major surgery within the last 4 weeks prior to starting study drug or who would not have fully recovered from previous surgery.
14. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients.
15. Patients with known hepatitis B (HBV) or C virus (HCV).
16. Ophthalmological conditions as follows:
• Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure)
• Current or past history of retinal pigment epithelial detachment / central serous retinopathy
• Current or past history of retinal vein occlusion
17. Patients with left ventricular ejection fraction (LVEF) < 55%.
18. Patients with cardiac comorbidities (myocardial infarct within 6 months of study start, NYHA class ≥ III, congestive heart failure or instable angina pectoris), uncontrolled hypertension (systolic blood pressure > 150 mm Hg and/or diastolic pressure > 90 mm Hg) or prolonged QTcF-interval (> 450 ms).
19. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.
20. Known hypersensitivity to one of the study drugs or excipients (i.e. lactose)
22. Concomitant or recent use (in the past 14 days) of strong inhibitors and inducers of CYP1A2, CYP2C19, CYP3A4, 3A5 and P-glycoprotein (P-gp)
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A: Incidence of dose-limiting toxicities (DLTs)
Part B: Progression free survival (PFS) per RECIST version 1.1
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
In part A: once the maximum tolerated dose of the combination has been established (no more than 1 out of 6 patients experienced a DLT at the MTD)
In part B: Data analysis will be done 30 months after inclusion of the first subject. |
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E.5.2 | Secondary end point(s) |
Incidence and severity of adverse events per CTCAEv4.03
Overall response rate, duration of response, time to response and overall survival (phase II only)
Plasma concentrations of selumetinib, afatinib and relevant metabolites |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
In part A: once the maximum tolerated dose of the combination has been established (no more than 1 out of 6 patients experienced a DLT at the MTD)
In part B: Data analysis will be done 30 months after inclusion of the first subject. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Dose finding/dose escalation |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
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 | 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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The end of the study will be upon completion of the follow-up period of the last patient. This will occur when either all the patients of PART B are deceased, every patient in PART B has completed the end of treatment assessments and has been followed for at least 18 months for overall survival after initiation of the last study treatment, or have been lost to follow-up or withdrew consent, whichever occurs first. |
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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 | |
E.8.9.1 | In the Member State concerned days | |