Chemonaive, Extensive Stage Lung Cancer, Small Cell Lung Cancer
Conditions
Keywords
Small cell lung cancer, Chemonaive, Bendamustine, Irinotecan, Etoposide, Carboplatin
Brief summary
Small cell lung cancer, or SCLC, constitutes approximately 15% of the 170,000 new cases of lung cancer diagnosed annually in the United States. Extensive-stage SCLC comprises two thirds of new cases and is generally considered sensitive to chemotherapy, despite a median time to progression of 4 months. SCLC is one of the most aggressive and lethal types of cancer, with a median survival of 9 months (range 7-11 months) in patients diagnosed with extensive disease. Overall, the majority of patients with SCLC die in less than 2 years (2-year survival rates generally less than 10%), and the 5-year survival rate is 2.3% for patients with extensive disease. The regimen of etoposide in combination with a platinum (cisplatin or carboplatin) is generally considered the standard of care although a recent Phase III trial suggests improved survival with the combination of cisplatin/irinotecan. Further evaluation of new agents in combination regimens attempting to overcome the intrinsic drug resistance seen in extensive-stage SCLC is warranted attempting to improve survival and achieve palliation of disease-related symptoms.
Detailed description
We are proposing a novel combination of bendamustine plus irinotecan followed by the standard regimen of etoposide with carboplatin. This will allow the investigation of response to the novel combination as well as any improvement in outcomes compared to historical controls.
Interventions
DRUGNovel Drug Combination
This novel drug combination includes: Bendamustine, Irinotecan, and Etoposide/Carboplatin. Subjects will be treated with irinotecan (150 mg/m2) infusion on Day 1 followed by infusion of bendamustine on Days 1 and 2 at increasing dose levels using a 3+3 design (starting dose of 80-mg/m2/d with 20 mg/mg/d incremental increase to max 120 mg/m2/d) (Regimen A). This will be repeated every 3 weeks for a total of 3 cycles. Restaging for response will be performed prior to the next regimen. * All subjects will then be given carboplatin (AUC 6) on day 1 and etoposide (100 mg/m2) on days 1, 2 and 3 (Regimen B). They will receive 3 cycles of this regimen every 3 weeks prior to restaging. * At the end (3 weeks after) of the sixth total round of chemotherapy, subjects will be re-evaluated for response, and will be followed-up for recurrent disease every 8 weeks.
Sponsors
National Comprehensive Cancer Network
University of Alabama at Birmingham
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single arm, open-label, Phase I - II trial with an initial dose escalation component and an expansion cohort of patients treated at the recommended Phase II dose.
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic diagnosis of extensive stage SCLC. * Measurable or assessable tumor parameters. * ECOG Performance Status 0-2. * Age between 18 and 79 years (in the State of Alabama \> 18). * Adequate bone marrow, liver and renal function, defined as: * Absolute neutrophil count (ANC) ≥ 1500/µL * Hemoglobin ≥ 8g/dl * Platelet count ≥ 100,000/µL * SGOT/SGPT ≤ 2 x upper limit of normal or ≤ 5 x upper limit of normal when liver metastases are present. * Total bilirubin value ≤ 2 x upper limit of normal. * Serum creatinine value ≤ 2 x upper limit of normal. * Fully recovered from any previous surgery (at least 4 weeks since major surgery) * Must have recovered from prior radiation therapy (at least 3 weeks) * All subjects must agree to practice approved methods of birth control (if applicable). A negative pregnancy test must be documented during the screening period for women of childbearing potential. * Must provide written informed consent and authorization to use and disclose health information (HIPAA). * Extensive-stage SCLC as defined as disease not confined to one hemithorax, including ipsilateral pleural effusion or pericardial effusion. * No prior chemotherapy.
Exclusion criteria
* Concurrent cancer chemotherapy, biologic therapy or radiotherapy. * Administration of any investigational drug within 28 days prior to administration of the current therapy. * Symptomatic brain metastases; those patients should be treated first with either whole brain radiation therapy or radiosurgery. * Concurrent serious infection. * Concomitant severe or uncontrolled underlying medical disease unrelated to the tumor, which is likely to compromise patient safety and affect the outcome of the study. * History of other malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off all therapy for a minimum of 2 years. * Neuropathy at baseline ≥ Grade 2. * Any evidence or history of hypersensitivity or other contraindications for the drugs used in this trial. * History of chronic diarrhea; or diarrhea (excess of 2-3 stools/day above normal frequency) in the past 2 weeks. * History of a positive serology for human immunodeficiency virus (HIV). * Psychiatric disorder that prevents patients from providing informed consent or following protocol instructions. * Pregnant or lactating women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose Limiting Toxicity Regimen A - Phase I | 9 weeks | The determination of the dose limiting toxicity as defined by The National Cancer Institute Common Toxicity Criteria version 3 as follows: grade 4 neutropenia \>5 days; grade 3/4 febrile neutropenia; grade 4 thrombocytopenia; or grade \>2 non-hematologic toxicities (except for nausea/vomiting, alopecia, or fatigue). |
| Number of Patients With Adverse Events - Phase II | 9 weeks | The degree of toxicity as defined by The National Cancer Institute Common Toxicity Criteria version 3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 7 months | Using the Response Evaluation Criteria in Solid Tumors (RECIST 2000), progression is defined as 20% or greater increase from the baseline tumor parameters or new lesions. |
Countries
United States
Participant flow
Recruitment details
Protocol Open to Accrual: April 2009, Primary Completion Date: May 2015 and Study Completion Date: May 2016. Recruitment location: University of Alabama at Birmingham and Georgia Cancer Specialists.
Pre-assignment details
We are proposing a novel combination of bendamustine plus irinotecan followed by the standard regimen of etoposide with carboplatin. This will allow the investigation of response to the novel combination as well as any improvement in outcomes compared to historical controls.
Participants by arm
| Arm | Count |
|---|---|
| Regimen A: Cohort I Bendamustine 80 mg/m2 (Day 1,2) Participants were treated with irinotecan at 150 mg/m2 on day 1 followed by bendmustine on days 1 and 2 at increasing dose levels using a 3 + 3 design. The initial dose of bendamustine was 80 mg/m2 with incremental 20 mg/m2 dose escalation to a maximum of 120 mg/m2. This was repeated every 21 days for a total of 3 cycles. | 3 |
| Regimen A: Cohort II Bendamustine 100 mg/m2 (Day 1,2) Participants were treated with irinotecan at 150 mg/m2 on day 1 followed by bendmustine on days 1 and 2 at increasing dose levels using a 3 + 3 design. The initial dose of bendamustine was 100 mg/m2 with incremental 20 mg/m2 dose escalation to a maximum of 120 mg/m2. This was repeated every 21 days for a total of 3 cycles. | 6 |
| Regimen A: Cohort III Bendamustine 120 mg/m2 (Day 1,2) Participants were treated with irinotecan at 150 mg/m2 on day 1 followed by bendmustine on days 1 and 2 at increasing dose levels using a 3 + 3 design. The initial dose of bendamustine was 120 mg/m2 with incremental 20 mg/m2 dose escalation to a maximum of 120 mg/m2. This was repeated every 21 days for a total of 3 cycles. | 6 |
| Regimen A: Cohort IV Bendamustine 100 -120 mg/m2 (Day 1,2) Participants were treated with irinotecan at 150 mg/m2 on day 1 followed by bendmustine on days 1 and 2 at increasing dose levels using a 3 + 3 design. Bendamustine was given at 100 - 120 mg/m2. This was repeated every 21 days for a total of 3 cycles. | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Irinotecan & Bendamustine | Death | 0 | 0 | 0 | 2 |
| Irinotecan & Bendamustine | Physician Decision | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Regimen A: Cohort I Bendamustine 80 mg/m2 (Day 1,2) | Regimen A: Cohort II Bendamustine 100 mg/m2 (Day 1,2) | Regimen A: Cohort III Bendamustine 120 mg/m2 (Day 1,2) | Regimen A: Cohort IV Bendamustine 100 -120 mg/m2 (Day 1,2) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 6 Participants | 5 Participants | 13 Participants | 27 Participants |
| Region of Enrollment United States | 3 participants | 6 participants | 6 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 30 |
| other Total, other adverse events | 15 / 30 |
| serious Total, serious adverse events | 15 / 30 |
Outcome results
Primary
Number of Participants Experiencing Dose Limiting Toxicity Regimen A - Phase I
The determination of the dose limiting toxicity as defined by The National Cancer Institute Common Toxicity Criteria version 3 as follows: grade 4 neutropenia \>5 days; grade 3/4 febrile neutropenia; grade 4 thrombocytopenia; or grade \>2 non-hematologic toxicities (except for nausea/vomiting, alopecia, or fatigue).
Time frame: 9 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Novel Drug Combination | Number of Participants Experiencing Dose Limiting Toxicity Regimen A - Phase I | Phase I - Cohort I | 0 participants |
| Novel Drug Combination | Number of Participants Experiencing Dose Limiting Toxicity Regimen A - Phase I | Phase I - Cohort II | 1 participants |
| Novel Drug Combination | Number of Participants Experiencing Dose Limiting Toxicity Regimen A - Phase I | Phase I - Cohort III | 1 participants |
Primary
Number of Patients With Adverse Events - Phase II
The degree of toxicity as defined by The National Cancer Institute Common Toxicity Criteria version 3.
Time frame: 9 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Novel Drug Combination | Number of Patients With Adverse Events - Phase II | 8 participants |
Secondary
Progression Free Survival
Using the Response Evaluation Criteria in Solid Tumors (RECIST 2000), progression is defined as 20% or greater increase from the baseline tumor parameters or new lesions.
Time frame: 7 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Novel Drug Combination | Progression Free Survival | 6.0 months |