Non-small Cell Lung Cancer
Conditions
Keywords
Vorinostat, NSCLC, EGFR, Erlotinib
Brief summary
This is an open label, non-randomized, sequential, phase I/II trial in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) with EGFR mutations after progression to Erlotinib. The study will have two parts. The first part (phase I) will be a dose finding (MTD) study to be implemented at three hospitals. The second part of the study (phase II) will asses the safety and efficacy of the combination. In this second part (phase II) patients will be treated with oral Erlotinib 150 mg P.O daily plus oral Vorinostat administered according to the results of the phase I. The study endpoints to be evaluated will include safety and response rate (RR) as primary endpoints and clinical benefit rate (CBR), time to progression, time to response, response duration and progression free survival as secondary endpoints. All the patients (phase I and II) will be treated until progression disease, unacceptable toxicity or withdrawal of the consent, and will be treated at the discretion of the principal investigator.
Detailed description
SAMPLE: Patients must have histologically-confirmed diagnosis of stage IIIB or IV NSCLC, with prior treatment with Erlotinib. In the phase I study the upper expected number of patients will be eighteen. In the phase II thirty two eligible patients will be included in the study. The enrollment period will be approximately 1.5 years. All patients will be treated with Erlotinib and Vorinostat regimen. Participating hospitals will be those of the Spanish Lung Cancer Group (SLCG). For the phase I portion, there will be 3 sites: Dr. Noemi Reguart and Dr. Rafael Rosell, Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona (Barcelona, Spain), Dr. Felip Cardenal, Institut Catalan d'Oncologia. Centre Sanitari i Universitari de Bellvitge (CSUB), Hospitalet de Llobregat (Barcelona, Spain) and Dr. Lola Isla, Hospital Clinico Lozano Blesa, (Zaragoza, Spain) For the phase II portion, 10 hospitals (adding 7 to the first 3) from the Spanish Lung Cancer Group (SLCG) will be involved. Hospitals will be included during phase I study. OBJECTIVES AND HYPOTHESES Primary Phase I (1) To determine the MTD of oral vorinostat in combination with erlotinib and to ensure that this treatment is sufficiently safe and tolerable to permit further study. Phase II (1) To determine the percentage of patients free of progression at 12 weeks. Hypothesis: We considered that treatment was effective if we obtained a percentage of patients free of progression at 12 weeks higher than 60%. Secondary (1) To determine the CBR (clinical benefit rate), response rate, time to progression, time to response, response duration, and progression free survival in patients treated with vorinostat and erlotinib in combination. Hypothesis: CBR should be of at least 25% and it will include stable disease for at least 3 months and objective RECIST response for at least 4 weeks. Exploratory endpoints Molecular analysis: Main Objective: analysis of EGFR mutations (in exons 19, 20 and 21) in serum samples at baseline (before treatment), at three months of treatment and at the end of the treatment. Secondary Objectives: retrospective analysis of molecular markers potentially related to drug sensitivity such as E-catherin protein expression, thioredoxin serum levels; Hsp70; methylation of 14-3-3r and CHFR.
Interventions
DRUGVorinostat plus Erlotinib
Phase I: Dose level 1: 300 mg V d1-7 every 21 days plus 100 mg E daily Dose level 2: 400 mg V d1-7 every 21 days plus 100 mg E daily Dose level 2b: 300 mg V d1-7 and 15-21 every 28 days plus 100 mg E daily Dose level 3: 400 mg V d1-7 and 15-21 every 28 days plus 150 mg E daily Phase II: Dose level 3: 400 mg V d1-7 and 15-21 every 28 days plus 150 mg E daily
Sponsors
Merck Sharp & Dohme LLC
Spanish Lung Cancer Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed NSCLC 2. Diagnosis of advanced stage IIIB with pleural effusion or IV NSCLC 3. Previous disease progression after \>= 3 months treatment with Erlotinib. Must tolerate erlotinib dose of 150 mg daily during the prior month. 4. Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21 (Exon 19 mutations characterized by in-frame deletions (747-750), and Exon 21 mutations resulting in L858R substitutions). 5. At least 18 years old. 6. Measurable disease as defined by the presence of at least one lesion that can be accurately measured in at least one dimension using RECIST guidelines. 7. At least 4 weeks from any prior major surgery or radiation therapy and have adequately recovered from the toxicities and/or complications 8. ECOG performance status 0 to 2 9. Adequate bone marrow function without the current use of colony stimulating factors. 10. Adequate coagulation function. 11. Adequate liver function 12. Adequate renal function 13. Non-sterilized premenopausal female, pregnancy test must be performed and patient must agree to use barrier methods of contraception. Male patients must agree to use an adequate method of contraception. 14. Available for periodic blood sample analyses, study related assessments 15.Patient has the ability to understand and willingness to sign the informed consent form. 16.Patient is able to read, understand, and complete the study questionnaires.
Exclusion criteria
1. Patient has been treated with any investigational agent for any indication within 4 weeks of study treatment. 2. Patient previously treated with Vorinostat or any other HDAC inhibitor for any indication in the previous 30 days. 3. Patient has history of hypersensitivity or intolerance to Erlotinib. 4. Patient has an active infection or has received intravenous antibiotic, antiviral or antifungal medications with 2 weeks 5. Patient with symptomatic central nervous system metastases with or without corticosteroids treatment. 6. Inability to take and/or tolerate oral medications. 7. Patient has known active hepatitis B or C infection,(HIV) HIV-related malignancy. 8. Pregnant or breastfeeding. 9. Patient with a history of gastrointestinal disease, surgery 10. Patient with uncontrolled undercurrent illness or circumstances that could limit compliance with the study. 11. History of malignancy except for inactive non-melanoma skin cancer and/or in situ carcinoma of the cervix, or other solid tumor treated curatively and without evidence of recurrence for at least 5 years prior to study enrollment. 12. Patient has had prescription or non-prescription drugs or other products known to influence CYP3A4 that cannot be discontinued prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival Rate at 12 Weeks | From date of first day of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 weeks | Progression Free Survival was defined as time from first treatment until progression or death from any cause. |
| Maximum Tolerated Dose (MTD) of Oral Vorinostat Phase I | Up to 24 weeks for each dosing cohort | In the phase I, a classic 3 + 3 dose escalation method with 3 patients treated initially at each dose level was used. MTD was determined by testing on dose escalation cohorts: continuous full dose of erlotinib 150 mg orally (p.o.) in a daily administration(QD) and escalating doses of vorinostat p.o. at three dose levels:300 mg QD 7 days every 21 days, 400 mg QD 7 days every 21 days,and 400 mg QD, 7 days every other week. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in less than or equal to 1 in 6 patients. DLTs were defined as any Vorinostat-related Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE 3.0) Grade 3 or 4 adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the date of study inclusion until end of follow up, up to 36 months. | Overall survival was defined as time from study inclusion until death |
| Time to Progression | From the date of randomization until end of follow up, up to 36 months. | The time to progression has been defined as the time that elapses, in months, since the patient begins study treatment until the patient progresses or dies from the disease, the first thing that occurs. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Countries
Spain
Participant flow
Recruitment details
Between December 2007 and November 2010 the patients were enrolled in the phase I-II trial.
Pre-assignment details
Screening details: Histologically confirmed NSCLC Diagnosis of advanced stage IIIB with pleural effusion or IV NSCLC Previous disease progression after \>= 3 months treatment with Erlotinib. Must tolerate erlotinib dose of 150 mg daily during the prior month. Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat Plus Erlotinib Phase II Vorinostat plus erlotinib
Phase II:
Dose level 3: 400 mg V d1-7 and 15-21 every 28 days plus 150 mg E daily | 25 |
| Vorinostat Plus Erlotinib Phase I Drug: Vorinostat plus Erlotinib
Phase I:
Dose level 1: 300 mg V d1-7 every 21 days plus 100 mg E daily | 3 |
| Vorinostat Plus Erlotinib Phase I Level 2 Drug: Vorinostat plus Erlotinib
Phase I:
Dose level 2: 400 mg V d1-7 every 21 days plus 100 mg E daily Dose level 2b: 300 mg V d1-7 and 15-21 every 28 days plus 100 mg E daily | 3 |
| Vorinostat Plus Erlotinib Phase I Level 3 Drug: Vorinostat plus Erlotinib
Phase I:
Dose level 3: 400 mg V d1-7 and 15-21 every 28 days plus 150 mg E daily | 2 |
| Total | 33 |
Baseline characteristics
| Characteristic | Vorinostat Plus Erlotinib Phase I Level 3 | Vorinostat Plus Erlotinib Phase I Level 2 | Vorinostat Plus Erlotinib Phase I | Vorinostat Plus Erlotinib Phase II | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 12 | 54.67 years STANDARD_DEVIATION 9.74 | 60 years STANDARD_DEVIATION 9.93 | 60.8 years STANDARD_DEVIATION 10.1 | 60.12 years STANDARD_DEVIATION 10.44 |
| ECOG ECOG 0 | 1 participants | 2 participants | 2 participants | 8 participants | 13 participants |
| ECOG ECOG 1 | 1 participants | 1 participants | 1 participants | 15 participants | 18 participants |
| ECOG ECOG 2 | 0 participants | 0 participants | 0 participants | 2 participants | 2 participants |
| EGFR mutations blood Del 19 | 1 participants | 2 participants | 3 participants | 7 participants | 13 participants |
| EGFR mutations blood L858R | 1 participants | 1 participants | 0 participants | 5 participants | 7 participants |
| EGFR mutations blood NE | 0 participants | 0 participants | 0 participants | 7 participants | 7 participants |
| EGFR mutations blood Wild type | 0 participants | 0 participants | 0 participants | 6 participants | 6 participants |
| EGFR tumor mutations Del 19 | 2 participants | 2 participants | 2 participants | 15 participants | 21 participants |
| EGFR tumor mutations L858R | 0 participants | 1 participants | 1 participants | 10 participants | 12 participants |
| Histology Adenocarcinoma | 2 participants | 3 participants | 3 participants | 21 participants | 29 participants |
| Histology Large cell | 0 participants | 0 participants | 0 participants | 2 participants | 2 participants |
| Histology Squamous | 0 participants | 0 participants | 0 participants | 2 participants | 2 participants |
| Median prior treatments Four or more | 0 participants | 0 participants | 0 participants | 6 participants | 6 participants |
| Median prior treatments Not recorded | 2 participants | 3 participants | 3 participants | 0 participants | 8 participants |
| Median prior treatments One | 0 participants | 0 participants | 0 participants | 7 participants | 7 participants |
| Median prior treatments Three | 0 participants | 0 participants | 0 participants | 8 participants | 8 participants |
| Median prior treatments Two | 0 participants | 0 participants | 0 participants | 4 participants | 4 participants |
| Metastatic sites Not recorded | 2 participants | 3 participants | 3 participants | 0 participants | 8 participants |
| Metastatic sites One | 0 participants | 0 participants | 0 participants | 5 participants | 5 participants |
| Metastatic sites Three or more | 0 participants | 0 participants | 0 participants | 10 participants | 10 participants |
| Metastatic sites Two | 0 participants | 0 participants | 0 participants | 10 participants | 10 participants |
| Region of Enrollment Spain | 2 participants | 3 participants | 3 participants | 25 participants | 33 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 16 Participants | 19 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 2 Participants | 9 Participants | 14 Participants |
| Smoking habits Current | 0 participants | 0 participants | 0 participants | 3 participants | 3 participants |
| Smoking habits Former 1-5 years | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Smoking habits Former < 1 year | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Smoking habits Former > 5 years | 0 participants | 0 participants | 0 participants | 4 participants | 4 participants |
| Smoking habits Never | 0 participants | 0 participants | 0 participants | 16 participants | 16 participants |
| Smoking habits Not recorded | 2 participants | 3 participants | 3 participants | 0 participants | 8 participants |
| Stage IIIB | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Stage IV | 2 participants | 3 participants | 3 participants | 24 participants | 32 participants |
| T790M blood NE | 2 participants | 3 participants | 3 participants | 7 participants | 15 participants |
| T790M blood Positive | 0 participants | 0 participants | 0 participants | 7 participants | 7 participants |
| T790M blood Wild type | 0 participants | 0 participants | 0 participants | 11 participants | 11 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 0 / 3 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 22 / 25 | 3 / 3 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 16 / 25 | 0 / 3 | 1 / 3 | 2 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Oral Vorinostat Phase I
In the phase I, a classic 3 + 3 dose escalation method with 3 patients treated initially at each dose level was used. MTD was determined by testing on dose escalation cohorts: continuous full dose of erlotinib 150 mg orally (p.o.) in a daily administration(QD) and escalating doses of vorinostat p.o. at three dose levels:300 mg QD 7 days every 21 days, 400 mg QD 7 days every 21 days,and 400 mg QD, 7 days every other week. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in less than or equal to 1 in 6 patients. DLTs were defined as any Vorinostat-related Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE 3.0) Grade 3 or 4 adverse events.
Time frame: Up to 24 weeks for each dosing cohort
Population: Fourteen patients were treated with escalation doses of vorinostat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat Plus Erlotinib Phase II | Maximum Tolerated Dose (MTD) of Oral Vorinostat Phase I | 400 mg |
Primary
Progression Free Survival Rate at 12 Weeks
Progression Free Survival was defined as time from first treatment until progression or death from any cause.
Time frame: From date of first day of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 weeks
Population: Efficacy analysis PFSR12w population: all patients who have received at least one dose of study medication have been included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat Plus Erlotinib Phase II | Progression Free Survival Rate at 12 Weeks | 28 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as time from study inclusion until death
Time frame: From the date of study inclusion until end of follow up, up to 36 months.
Population: Efficacy analysis: all patients who have received at least one dose of study medication have been included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat Plus Erlotinib Phase II | Overall Survival | 10.3 Month |
Secondary
Time to Progression
The time to progression has been defined as the time that elapses, in months, since the patient begins study treatment until the patient progresses or dies from the disease, the first thing that occurs. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From the date of randomization until end of follow up, up to 36 months.
Population: Efficacy analysis: all patients who have received at least one dose of study medication have been included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vorinostat Plus Erlotinib Phase II | Time to Progression | 1.8 Month |