A phase Ib, open-label, multi-center, dose escalation and expansion study of an orally administered combination of BKM120 plus MEK162 in adult patients with selected advanced solid tumors
- Conditions
- cancer10027655Solid tumors
- Registration Number
- NL-OMON43645
- Lead Sponsor
- Array BioPharma Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 10
Patients with the following histologically/cytologically confirmed, advanced solid tumor for whom no standard therapy exists:
• Advanced pancreatic cancer (irrespective of KRAS or B-RAF mutation status).
• Advanced colorectal with KRAS, NRAS or BRAF mutations.
• Advanced melanoma with NRAS or BRAF mutations.
• Advanced NSCLC with KRAS mutation.
• Other advanced solid tumors with documented KRAS, NRAS or BRAF mutations.
• Triple negative breast cancer.
• Advanced NSCLC patients with EGFR activating mutations, who have progressed on a prior EGFR TKI based regimen and NSCLC patients known to have documented T790M activating mutations (expansion-arm only)
Measurable or non-measurable, but evaluable disease as determined by RECIST.
ECOG (WHO) performance status 0-2.
Adequate organ function and laboratory parameters:
• Absolute Neutrophil Count >= 1.5 x 109/L
• Hemoglobin >= 10 g/dl (=6.2 mmol/L)
• Platelets >= 100 x 109/L
• AST/SGOT and/or ALT/SGPT <= ULN (upper limit of normal) or <= 3.0 x ULN if liver metastases are present.
• Serum bilirubin <= ULN (or <= 1.5 x ULN if liver metastases are present; or total bilirubin <= 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome)
• Serum lipase <= ULN
• Fasting glucose levels < 7.0 mmol/L (126 mg/dL) or 2-hrs glucose < 11.1 mmol/L (200 mg/L) during OGTT
• Calculated or directly measured Creatinin Clearance * 50% LLN
Recovery from all adverse events of previous anti-cancer therapies, including surgery and radiotherapy, to baseline or to Grade <= 1, except for alopecia and < Grade 2 sensory peripheral neuropathy.
Adequate cardiac function
• LVEF >= 50%
• NYHA Class <= 2
• QTc interval <= 480ms
Patients with primary CNS tumor. Patients with clinically stable metastatic CNS tumors, not receiving steroid therapy and is not receiving anti-convulsive medications are eligible.
Prior systemic anti-cancer treatment:
• cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment.
• biologic therapy (e.g., antibodies) within a period of time which is <= 5 t1/2 or <= 4 weeks prior to starting study treatment.
• continuous or intermittent small molecule therapeutics within a period of time which is <= 5 t1/2 or <= 4 weeks prior to starting study treatment.
• any other investigational agents within a period of time that is less than the cycle length used for that treatment or <= 4 weeks prior to starting study treatment.
Prior radiotherapy to > 30% of bone marrow.
Major surgery <= 4 weeks prior to starting study treatment.
History of prior significant toxicity from another MEK- or PI3K pathway inhibitor requiring discontinuation of treatment.
Prior treatment with combinations of MEK and PI3K/mTOR/ AKT inhibitors.
Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
• History/evidence of acute coronary syndromes (including MI, unstable angina, CABG, coronary angioplasty, or stenting), < 6 months prior to screening.
• Symptomatic heartfailure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality, e.g. congential long QT syndrome, high-grade/complete AV-blockage.
• Uncontrolled arterial hypertension defined by BP > 140/100 mmHg at rest.
Patients with diabetes mellitus.
Mood disorders as judged by the Investigator or a Psychiatrist, or meets the cut-off score of >= 10 in the PHQ-9 depression scale or a cut-off of >= 15 in the GAD-7 mood scale, respectively, or selects a positive response of *1, 2, 3* to question number 9 in the PHQ-9 depression scale (potential for suicidal thoughts) and any of the following:
• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
• >=CTCAE grade 3 anxiety
History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or ophthalmopathy at baseline that would be considered a risk factor for CSR/RVO
Any other condition that would, in the investigator*s judgment, contraindicate patient*s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Determine the MTD and/or RP2D of BKM120: Incidence of Dose Limiting Toxicities</p><br>
- Secondary Outcome Measures
Name Time Method <p>Safety and tolerability: Adverse and serious adverse drug reactions, changes in<br /><br>hematology and chemistry values and assessment of physical and neurological<br /><br>examinations, vital signs and electrocardiograms.<br /><br>Preliminary anti-tumor activity of the combination: ORR (Overall Response<br /><br>Rate), DOR (Duration of Response), TTR (Time To Response) and PFS (Progression<br /><br>Free Survival) according to RECIST.<br /><br>PK profile of the combination: Time vs. plasma concentration profiles; basic PK<br /><br>parameters of BKM120 and MEK162 and its primary active metabolite.<br /><br>Effects of BKM120 and MEK162 on PI3K and MAPK signaling in skin and tumor<br /><br>tissue: Pharmacodynamic: ΔCT values of DUSP6, SPRY4 and BMF gene expression<br /><br>and H-scores for phospho-Akt/S6/4E-BP1, phospho-MEK/ERK, Ki-67 and PARP pre-<br /><br>vs. post-dose</p><br>