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A Phase I/II Study of Paclitaxel, Carboplatin and YM155 (Survivin Suppressor) in Subjects With Solid Tumors (Phase I) and Advanced Non-Small Cell Lung Carcinoma (Phase II)

Phase 1/Phase 2
18 Years
Not Enrolling
NSCLC, Solid Tumors

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Trial Information

A Phase I/II Study of Paclitaxel, Carboplatin and YM155 (Survivin Suppressor) in Subjects With Solid Tumors (Phase I) and Advanced Non-Small Cell Lung Carcinoma (Phase II)


- 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

- 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.


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.


- Open label phase I/II trial

- Following a Simon two-stage optimal design

Inclusion Criteria


Response should be YES

Phase 1 and 2:

1. Has a signed consent/assent been obtained by the patient or parent/legal guardian?

2. Is a male or female greater than or equal to 18 years old?

3. If patient has brain metastases, is it asymptomatic and does not require steroids or
antiepileptic mediations?

4. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky >

5. Has adequate bone marrow, renal, and hepatic function:

1. Absolute neutrophil count (ANC) greater than or equal to 1,500/m^3?

2. Hemoglobin greater than or equal to 10.0g/dl?

3. Platelets greater than or equal to 100,000/m^3?

4. Has adequate renal function defined as serum creatinine < upper limit of normal
(ULN) or calculated creatinine clearance > 60 mL/min?

5. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)
and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)
less than or equal to 2.5 times ULN?

6. Total bilirubin less than or equal to 1.5 times ULN (in patients with evidence
of Gilberts disease, elevated bilirubin should not be related to tumor or other
liver diseases and should be less than or equal 2 times upper limit of normal)?

6. Has negative human immunodeficiency virus (HIV) test?

7. If female, has negative pregnancy test?

8. Both male and female patients are willing to consent to using effective contraception
(hormonal, barrier method or abstinence) prior to study entry, while on treatment and
at least 3 months thereafter?

Phase 1 only:

1. Has recurrent or advanced cancer for whom standard therapy offers no curative
potential and also for patients for whom the carboplatin/paclitaxel regimen is
considered standard of care?

2. Has received no more than one previous chemotherapy regimen?

3. Has evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST)

Phase 2 only:

1. Has histological or cytological evidence of non small cell lung cancer?

2. Has evidence of metastatic disease or stage IIIB non small cell lung cancer (NSCL)
with pleural effusion is required?

3. Has no prior chemotherapy for advanced lung cancer?

Note: Patients who received adjuvant or neo-adjuvant chemotherapy more than 12 months
prior will be eligible?

4. Has measurable disease, defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded) as > 20 mm with
conventional techniques or as > 10 mm with spiral computed tomography (CT) scan?


Response should be NO

1. Has any of the following within 6 months prior to study enrollment: myocardial
infarction, unstable angina pectoris or uncontrolled angina pectoris, uncontrolled
hypertension that is not controllable with antihypertensives, coronary/peripheral
artery bypass graft, New York Heart Association (NYHA) class III or IV congestive
heart failure, clinically significant peripheral vascular disease (Grade II or

2. Has history of stroke or transient ischemic attack within 6 months?

3. Has history of pulmonary embolism, deep venous thrombosis or other thrombo-embolic
event within 6 months?

4. Has psychiatric or neurologic illness that would limit compliance with study

5. Has severe active infection within 14 days requiring use of intravenous antibiotics
before beginning treatment?

6. Has received any other investigational agents within 30 days of the start of

7. Has history of an active malignancy unless curatively treated and risk of recurrence
of < 5% at five years, with the exception of:

1. Adequately treated in situ carcinoma of the cervix

2. Non-melanomatous skin cancers (basal or squamous cell)?

8. Has history of severe hypersensitivity reaction to compounds of similar chemical or
biologic composition to carboplatin, paclitaxel, or medicines of similar composition
to YM155?

9. Has history of a major surgical procedure, open biopsy, or a significant traumatic
injury within 14 days prior to commencing treatment, or the anticipation of the need
for a major surgical procedure during the course of the study?

10. Has other serious illness, medical condition or significant laboratory abnormality
that may cause undue risk for the subject's safety, inhibit protocol participation,
or interference with interpretation of study results, and in the judgment of the
investigator would make the subject inappropriate for entry into this study?

11. Phase 2 only: Has mixed tumor of any histology including small cell lung cancer?

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase 1 Safe and Tolerable Phase 2 Dose.

Outcome Description:

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 2 dose is based upon dose limiting toxicities experienced during cycle 1.

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Giuseppe Giaccone, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

February 2010

Completion Date:

December 2012

Related Keywords:

  • Solid Tumors
  • Solid Tumors
  • YM155
  • Survivin
  • Non Small-Cell Lung Cancer
  • Solid Tumor
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Neoplasms



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