Phase I/II Study of the P13Kinase Inhibitor BKM120 Given in Combination With Panitumumab in Patients With Metastatic or Advanced RAS-Wild Type Colorectal Cancer.
- Histologic proof of a primary colorectal cancer which is recurrent or metastatic.
- Tumour must be confirmed to be K-Ras wild type (i.e. no K-Ras mutation found) by
means of mutation analysis performed on representative samples of diagnostic tumour
tissue by the standard regional or provincial laboratory and be eligible to receive
standard panitumumab treatment as per local guidelines (i.e. must have failed, or
have been unable to receive prior irinotecan, oxaliplatin and thymidylate synthase
inhibitor therapy). Note: Archival tumour samples are acceptable for K-Ras mutation
- In the phase I portion of the trial, patients may have measurable OR non-measurable
disease. Patients whose only evidence of disease progression is tumour marker
elevation are not eligible.
- In the phase II portion of the trial, all patients must have measurable disease as
defined by RECIST 1.1.
The criteria for defining measurable disease are as follows:
Chest X-ray ≥ 20 mm CT/MRI scan (with slice thickness of < 5 mm) ≥ 10 mm → longest
diameter Physical exam (using calipers) ≥ 10 mm Lymph nodes by CT scan ≥ 15 mm → measured
in short axis
Patients must have recovered from recent surgery, chemotherapy and/or radiation therapy
and significant toxicity must have recovered to ≤ grade 2. At least 4 weeks must have
elapsed from major surgery and radiation therapy, unless the radiation is low dose, does
not involve mucosa and is non-myelosuppressive. Patient must have recovered (grade 0-1)
from all reversible toxicity related to prior chemotherapy and have adequate washout from
prior chemotherapy and investigational agents as follows: Washout period is the longest of
one of the following:
1. two weeks
2. standard cycle length of prior regimen (i.e. 21 days for irinotecan q 3 weeks).
3. 10 half-lives for investigational drugs.
ECOG performance status of 0, 1 or 2.
- Laboratory Requirements: (must be done within 7 days prior to registration)
Hematology: Absolute granulocytes (AGC) ≥ 1.0 x 109/L Platelets ≥ 100 x 109/L
Hemoglobin ≥ 90 g/L Chemistry: Serum creatinine ≤ 1.5 x UNL OR Creatinine clearance ≥
50 ml/min Bilirubin * ≤ UNL AST and ALT ≤ 3.0 x UNL Potassium ≤ UNL Calcium ≤ UNL
Magnesium ≥ 0.5 mmol/L (may be achieved with supplementation) Blood glucose (fasting)
< 7.8 mmol/L Coagulation: INR ≤ 2 x UNL (* direct, if patient known to have Gilberts)
- Patient must consent to provision of, and investigator(s) must confirm access to and
agree to submit at the request of the NCIC CTG Central Tumour Bank, a representative
formalin fixed paraffin block of tumour tissue in order that the correlative marker
assays may be conducted. Where local centre regulations prohibit submission of blocks
of tumour tissue, the approval of the NCIC CTG must be sought prior to registration
of the first patient to allow a predetermined number of slides of representative
tumour tissue to be substituted in response to the Central Tumour Bank request.
Failure to submit any tissue samples on request will result in the patient being
considered ineligible. Where no previously resected or biopsied tumour tissue exists,
on the approval of the NCIC CTG, the patient may still be considered eligible for the
- Age ≥ 18 years. (Note that the lower age limit at each centre will be determined by
that centre's policy regarding the age at which an individual may sign their own
- Women of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to registration. Patients of reproductive potential must agree
to use highly effective contraception as follows:
- Female study subjects: during study and for 6 months after final dose of study
- Male study subjects: during study and until 16 weeks after final dose of study
- Female partner of male study subject: during study and until 16 weeks after final
dose of study therapy
- Patient consent for trial participation must be obtained according to local
Institutional and/or University Human Experimentation Committee requirements. It will
be the responsibility of the local participating investigators to obtain the
necessary local clearance, and to indicate in writing to the NCIC CTG Study
Coordinator that such clearance has been obtained, before the trial can commence in
that centre. Because of differing requirements, standard consent forms for the trial
will not be provided but sample forms are provided. A copy of the initial full board
Research Ethics Board (REB) approval and approved consent forms must be sent to the
central office. The patient must sign the consent forms prior to registration. Please
note that the consent forms for this study must contain a statement which gives
permission for qualified representatives of the NCIC CTG, monitoring agencies and
regulatory authorities to review patient records.
- Patients must be accessible for treatment and follow-up. Investigators must assure
themselves the patients registered on this trial will be available for complete
documentation of the treatment, adverse events, and follow-up. Patients enrolled in
this trial must be treated and followed at the participating centre. This implies
there must be a reasonable geographical limit (for example: 2 hour's driving
distance) placed on the patients being considered for this trial.
- Protocol treatment is to begin within 5 working days of patient registration.
- A history of other malignancies, except: adequately treated non-melanoma skin cancer,
curatively treated in-situ cancer of the cervix, or other solid tumours curatively
treated with no evidence of disease for > 5 years.
- Women who are pregnant or breastfeeding.
- Any active disease condition which would render the protocol treatment dangerous or
impair the ability of the patient to receive protocol therapy (e.g. chronic
pancreatitis, active chronic hepatitis, etc.).
- Any condition (e.g. psychological, geographical, etc.) that does not permit
compliance with the protocol.
- Uncontrolled or significant cardiovascular disease including:
- Myocardial infarction within 12 months;
- Uncontrolled angina within 6 months;
- Clinically significant congestive heart failure;
- TIA or other ischemic event within 12 months;
- Severe cardiac valve dysfunction
- Phase I: Patients may not be diabetic
- Phase II: Patients may be diabetic, but must have controlled diabetes (fasting
glucose < 7.8 mmol/L)
- Patient has any of the following mood disorders:
- 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
- score of ≥ 10 in the PHQ-9
- score of ≥ 15 in the GAD-7 mood scale
- patient selects a positive response of '1, 2, 3' to question number 9 (suicidal
ideation) in the PHQ-9
- Symptomatic metastases in the central nervous system. Subjects with signs or symptoms
suggestive of brain metastasis are not eligible unless brain metastases are ruled out
by CT or MRI scans.
- Patients who have received prior EGFR or PI3 Kinase inhibitor therapy.
- Receipt of an investigational therapeutic agent within washout period defined in
section 5.1.4 of the protocol.
- Severe restrictive lung disease or radiological pulmonary findings of "interstitial
lung disease" on the baseline chest x-ray which, in the opinion of the investigator,
represents significant pathology.
- Patients with impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of BKM120 (e.g. ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
- Patients who are unable to swallow capsules.
- Patients on potent CYP3A Inhibitors/Inducers (must have discontinued > 7 days prior
to day 1) or therapeutic doses of warfarin like anticoagulants. Patients may receive
low molecular weight heparin if indicated.
- Patients receiving chronic treatment with steroids or another immunosuppressive
agent. Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive
airways diseases), eye drops or local injections (e.g. intra-articular) are allowed.
Patients who are on a stable low dose corticosteroids treatment (e.g. dexamethasone 2
mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment
- Ongoing ocular inflammation or infection.
- Patients with significant (> grade 2) symptomatic ophthalmologic abnormalities such
- Severe dry eye syndrome
- Keratoconjunctivitis sicca
- Patients with known HIV (testing not mandatory) infection.