Afatinib and selumetinib in advanced KRAS mutant positive and PIK3CA wildtype non-small cell lung cancer and colorectal cancer

Phase 1

• Conditions: 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.; MedDRA version: 21.1 Level: PT Classification code 10029520 Term: Non-small cell lung cancer stage IIIA System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1 Level: PT Classification code 10029522 Term: Non-small cell lung cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1 Level: PT Classification code 10029521 Term: Non-small cell lung cancer stage IIIB System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1 Level: PT Classification code 10059515 Term: Non-small cell lung cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1 Level: PT Classification code 10029515 Term: Non-small cell lung cancer recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1 Level: PT Classification code 10029518 Term: Non-small cell lung cancer stage II System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-001855-22-NL
• Lead Sponsor: etherlands Cancer Institute- Antoni van Leeuwenhoek Hospital

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2014-10-15
• Last Update Posted: 16 December 2019

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• Target Recruitment: 140

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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 160
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 160

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,

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified