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 can
Conditions
Interventions
Product Name: Selumetinib hydrogen sulphate
Product Code: AZD6244
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Selumetinib hydrogen sulfate
CAS Number: 943332-08-9
Current Sponsor code: AZD
Sponsors
Netherlands Cancer Institute- Antoni van Leeuwenhoek Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
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
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) 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 ;Secondary Objective: 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 ;Primary end point(s): Part A: Incidence of dose-limiting toxicities (DLTs) Part B: Progression free survival (PFS) per RECIST version 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. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;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. | — |
Countries
Netherlands
Contacts
Public ContactClinical Research Monitor
Carla Vianen
Outcome results
None listed