Clinical trial NCT01100931
Conditions: NSCLC Solid Tumors
Keywords: NSCLC Solid Tumors YM155 Survivin Non Small-Cell Lung Cancer Solid Tumor
Sponsor: National Cancer Institute (NCI)
Start date: 2010-02-01; Completion date: 2012-12-01
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Carboplatin-paclitaxel is a commonly used chemotherapy combination for advanced non-small-cell lung carcinoma (NSCLC) and other solid tumors. In a randomized clinical trial, the combination of carboplatin, paclitaxel, and the additional chemotherapy drug bevacizumab had a better response rate and survival compared to carboplatin and paclitaxel alone. However, this trial treated only patients with a specific diagnosis and treatment risks. Further research is needed to determine whether this combination is useful for other diagnoses.
* YM155 is a drug that targets a type of chemical often found in cancer cells. It has been investigated in several phase I and phase II clinical trials, and it has been shown to be well tolerated and moderately effective in treating advanced NSCLC in patients who had not responded well to one or two standard treatments.

Objectives:

\- To determine the efficacy of the combination of carboplatin, paclitaxel, and YM155 in the treatment of non-small-cell lung cancer.

Eligibility:

\- Individuals 18 years of age and older who have been diagnosed with advanced non-small-cell lung carcinoma or other solid tumors for which standard therapy is not likely to be effective.

Design:

* Before the start of the study, participants will be screened with a medical history, blood tests, imaging scans of the affected areas, tumor biopsies, and other tests as directed by the study doctors.
* Participants will be treated for six 21-day cycles, or 18 weeks of treatment. Each cycle will include blood tests and imaging studies as required.
* On day 1 of each cycle, participants will receive an infusion of paclitaxel and carboplatin, followed by a 4-day infusion of YM155 (through a portable electronic infusion pump).
* Participants will have a computed tomography scan or other imaging every other cycle (approximately every 6 weeks) to determine whether the therapy is affecting the cancer site.
* After the sixth cycle, participants will return for follow-up visits at least every 3 months, and will be asked to remain in contact with the researchers to allow further study of the long-term effects of the treatment.

Detailed description:
Background:

* Treatment with platinum-based doublet chemotherapy results in a median survival of 7 to 10 months in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
* Carboplatin-paclitaxel is a commonly used regimen in advanced NSCLC and other solid tumors. In a randomized clinical trial carboplatin, paclitaxel plus bevacizumab resulted in improved efficacy (response rate and survival) compared to carboplatin and paclitaxel alone but only patients with non-squamous histology and who were considered low risk of bleeding were treated. Improvement of survival was not confirmed in another randomized study with a different chemotherapy backbone.
* Novel treatment strategies need to be developed for advanced NSCLC.
* YM155 is a transcriptional inhibitor of survivin, an inhibitor of apoptosis protein. Pre-clinical activity of YM155 has been observed in several solid tumors, including NSCLC models and synergy was observed in combination with chemotherapeutic drugs, including carboplatin and paclitaxel.
* YM155 has been investigated in several phase I and phase II clinical trials and it has been shown to be well tolerated with the most common toxicities reported as being reversible and of grades 1 -2 in severity. In addition, as a monotherapy YM155 alone has shown modest antitumor activity in a phase II trial in advanced NSCLC in patients who had failed one or two prior chemotherapy lines.

Primary Objectives:

* In the Phase I portion of the study the primary objective will be to determine a safe and tolerable phase II dose of YM155 based upon dose limiting toxicities (DLTs) when YM155 is administered over 72 hours by continuous intravenous infusion (CIVI) every 3 weeks in combination with paclitaxel and carboplatin.
* In the Phase II portion of the study the primary objective will be to determine the objective response rate (ORR = partial response (PR)+ complete response (CR)) of YM155 in combination with carboplatin and paclitaxel in the first line treatment of patients with advanced NSCLC.

Secondary Objectives:

* In the Phase I portion of the study the secondary objective will be to determine the preliminary activity of the combination regimen based upon response rate as measured by response evaluation criteria in solid tumors \[RECIST\].
* In the Phase II portion of the study the secondary objectives will be to determine the median progression free survival (PFS), median overall survival (OS) and safety and tolerability of this combination regimen in this patient population.
* To assess expression of particular genes on the pretreatment tumor and pre/post treatment serum samples to evaluate the treatment effects and correlate them with clinical outcome.

Eligibility:

Phase I

\- The phase I portion of the trial will be open to all patients with recurrent or advanced cancer (NSCLC and other solid tumors) for whom standard therapy offers no curative potential and also in patients for whom the carboplatin / paclitaxel regimen is considered standard of care. Patients should have received no more than one previous chemotherapy regimen.

Phase II

* Pathologically confirmed stage IIIB (malignant pleural effusion) or intravenous (IV) or recurrent NSCLC.
* No previous chemotherapy for advanced lung cancer.
* Adequate organ and bone marrow function.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

Design:

* Open label phase I/II trial
* Following a Simon two-stage optimal design

Arms: arm 1: Phase I: Doses were given at different dose levels until the maximum tolerated dose (MTD) was reached. Dose level 1: 3.6 mg/m\^2, dose level 2:5 mg/m\^2 , dose level 3:6 mg/m\^2, dose level 4:8 mg/m\^2, dose level 5:10 mg/m\^2 (MTD), dose level 6:12 mg/m\^2. Doses were given by continuous intravenous infusion over 72 hours every 21 days.Three patients were enrolled at each dose level in the absence of dose limiting toxicity (DLT). A DLT is defined as adverse events occurring during the first cycle of therapy (e.g. every 21 days).

Phase II: 10 mg/m\^2 (MTD)intravenous infusion over 72 hours every 21 days.
Interventions: intervention 1: YM155 intervention 2: Carboplatin intervention 3: Paclitaxel
Intervention descriptions: intervention 1: Phase I: Doses were given at different dose levels until the maximum tolerated dose (MTD) was reached. Dose level 1: 3.6 mg/m\^2, dose level 2:5 mg/m\^2 , dose level 3:6 mg/m\^2, dose level 4:8 mg/m\^2, dose level 5:10 mg/m\^2 (MTD), dose level 6:12 mg/m\^2. Doses were given by continuous intravenous infusion over 72 hours every 21 days.Three patients were enrolled at each dose level in the absence of dose limiting toxicity (DLT). A DLT is defined as adverse events occurring during the first cycle of therapy (e.g. every 21 days).

Phase II: 10 mg/m\^2 (MTD)intravenous infusion over 72 hours every 21 days. intervention 2: Area under curve (AUC) of 6 intravenous on day 1 intervention 3: 200 mg/m\^2 intravenous on day 1

Protocol documents: