patients with metastatic colorectal cancer resistant to standard therapies and with O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation. MedDRA version: 14.1 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Interventions
Trade Name: TEMOZOLOMIDE TEVA*5CPS 140MG
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TEMOZOLOMIDE
CAS Number: 85622-93-1
Concentration unit: mg milligram(s)
Concentration type: up to
Conce
Sponsors
AZIENDA OSPEDALIERA OSPEDALE NIGUARDA CA' GRANDA (A.O. DI RILIEVO NAZIONALE)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Signed and dated IRB/IEC-approved Informed Consent Histologically or cytologically confirmed metastatic colorectal adenocarcinoma (mCRC) Willing to submit unstained archived tumor issue if such tissue is available for analysis from primary surgery or subsequently Willing to undergo pretreatment biopsy Availability of cancerous lesion for biopsy that is both: 1. In a location amenable to image-guided core biopsy; Of adequate size (i.e. diameter at least 1 cm) to permit MGMT and other biomarkers evaluation in sample per investigators judgment Presence of hypermethylation of MGMT promoter evaluated on primary tumor tissue (paraffin embedded block from previous surgery or biopsy). Previous standard treatments including: 5-FU/capecitabine, oxaliplatin, irinotecan in patients with mutated KRAS; 5-FU/capecitabine, oxaliplatin, irinotecan, cetuximab and/or panitumumab in patients with wildtype KRAS. Prior bevacizumab treatment is allowed. In order to be included the patients should have received standard available therapies (at least two lines of prior therapies for metastatic disease). Patients treated with oxaliplatin in adjuvant setting should have progressed during or within six months of adjuvant therapy completion. Presence of measurable disease by conventional techniques (CT scan or MRI), according to RECIST 1.1. Progressive disease confirmed by CT scan or MRI after previous standard treatment. Patients withdrawn from standard treatment due to unacceptable toxicity may be enrolled into the study Male or female adult patients ³ 18 years of age ECOG (WHO) performance status 0-1 Estimated life expectancy of at least 3 months Adequate liver function (evaluated within 7 days of starting study treatment): - Bilirubin = upper limit of normal (ULN) (if liver metastases are present, then = 1.5 ULN is allowed) - Albumin = 3.0 g/dL - AST (SGOT), ALT (SGPT) 1,500 cells/mm3 - Platelet count > 100,000 cells/mm3 - Hemoglobin > 9.0 g/dL Agreement upon the use of effective contraceptive methods prior to study entry since signing of the informed consent until at least 3 months after the last study drug administration, if men and women of child producing potential Able and willing to adhere to the study visit schedule and to the other protocol requirements Capability to swallow capsules intact (without chewing, crushing, or opening). Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 29 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 29
Exclusion criteria
Exclusion criteria: Prior treatment with dacarbazine or temozolomide Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to inclusion EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor),Tis (carcinoma in situ) and T1 (Tumor invading lamina propria)]Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication; Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed within a maximum of 7 days before start of treatment, and a negative pregnancy test result must be documented before start of treatment; Congestive heart failure > New York Heart Association (NYHA) class 2; Unstable angina (angina symptoms at rest), new-onset of angina (initiated within the last 3 months). Myocardial infarction less than 6 months before start of study medication. Arterial or venous thrombotic or embolic events such as cerebrovascular accidents (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of study medication Ongoing infection > grade 2 NCI-CTCAE version 3.0; Untreated, symptomatic brain metastases Non-healing wound, ulcer, or bone fracture; Renal failure requiring hemo-or peritoneal dialysis; Treatment with antiviral drugs for HBV, HCV or HIV positivity; Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results; Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the antitumor activity in terms of Progression Free Survival (PFS) at 12 weeks since the start of temozolomide in patients with mCRC after failure of at least 2 lines of prior therapy, including fluoropyrimidine-, irinotecan-, oxaliplatin- and, in case of KRAS wild-type, panitumumab- or cetuximab containing therapy;Secondary Objective: To assess additional measures of tumor control to further characterize the efficacy profile of temozolomide in mCRC patients To define the safety profile of temozolomide in these setting;Primary end point(s): PFS rate at 12 weeks, i.e. the proportion of patients known to be alive and progression free at 12 weeks or later since treatment start. The primary efficacy analysis will be performed on the proportion of treated patients in a progression free-status at 12 weeks.;Timepoint(s) of evaluation of this end point: 12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Confirmed Objective Response Rate (confirmed CR + PR) according to RECIST 1.1 · Disease Control Rate (Confirmed Objective Response Rate + SD rate). · Disease Control Duration. This endpoint is assessed in patients whose best tumor response is CR, PR or SD as the time from the date of treatment start to the date of first documentation of objective tumor progression, objective tumor recurrence, or of death due progressive disease, whichever comes first. Patients not in PD at the end of the per-protocol follow-up, or who have received other antitumor treatments before objective PD documentation, are considered as censored observations and included in the analysis. · PFS time calculated as the time from treatment start to the time of progression or to the time of death whichever comes first. Patients who at the end of the per-protocol follow-up will neither progress nor die will be censored at the time when they are lastly assessed as progression free · Time to Tumor Progression (TTP) overall profile. For the patients who have documented objective tumor progression or recurrence, or die due to PD, TTP will be calculated as the time from the date of treatment start to the date of first documentation of objective progression or recurrence or of death due to PD or of unknown cause, whichever comes first. Patients not in PD at the end of the per-protocol follow-up, or who have received other antitumor treatments before objective PD documentation, are considered as censored observations and included in the analysis. Overall Survival (OS), i.e. the time from the date of treatment start to the date of death from any cause. In the absence of documentation/confirmation of death, survival time is censored at the date of the last visit or contact documenting that the patient was still alive. · Overall safety profile, evaluated on the basis of laboratory and clinical safety parameters (i.e. hematology and blood chemistry, vital signs, and | — |
Countries
Italy
Contacts
Public ContactONCOLOGIA
ONCOLOGIA
Outcome results
None listed