Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib

NCT01070706

Last updated date
Study Location
Center for breast cancer, National Cancer Center
Goyang, Kyeonggido, 410-769, Korea, Republic of
Contact
1-800-718-1021

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1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Breast Cancer
Sex
Female
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

1. Age ≥ 18 years

2. ECOG performance status 0-2

3. Histologically confirmed and newly diagnosed breast cancer

4. Documented HER2/neu non-overexpressing or non-amplified disease

- 0-1+ by HER2 IHC or

- HER2 gene non-amplification by HER2 FISH

5. Clinical stage II or III operable breast cancer

6. Axillary node positivity determined by cytology

7. No prior hormonal, chemotherapy or radiotherapy is allowed

8. No breast operation other than biopsy to make diagnosis is allowed

9. Adequate hematologic, hepatic and renal function

- Absolute neutrophil count ≥ 1,500/μL

- Hemoglobin ≥ 10.0 g/dL

- Platelet ≥ 100,000/μL

- AST/ALT ≤ 2 X UNL (upper limit of normal)

- Total bilirubin ≤ 1.5 mg/dL

- Alkaline phosphatase ≤ 2 X UNL

- Serum creatinine ≤ 1.5 mg/dL

10. Adequate cardiac function LVEF ≥ 50% and within the institutional range of normal as measured by echocardiogram or MUGA scan within 4 weeks of enrollment

11. Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to registration

12. Normal mental function to understand and sign the consent

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


1. Patients with metastatic breast cancer


2. Patients who received hormonal, chemotherapy or radiotherapy for breast cancer


3. Patients who underwent surgery for breast cancer


4. Patients with T2N0, or inflammatory (T4d) breast cancer


5. Patients who have history of cancer other than in situ uterine cervix cancer or
nonmelanotic skin cancer


6. Patients with GI tract disease resulting in an inability to take oral medication,
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease,
ulcerative colitis)


7. Any of the following within the 12 months prior to starting study treatment


- severe, unstable angina


- Myocardial infarction


- Uncontrolled or symptomatic congestive heart failure


- coronary/peripheral artery bypass graft


- cerebrovascular accident including transient ischemic attack


- pulmonary embolism


8. Ongoing cardiac dysrhythmias of grade ≥2, atrial fibrillation of any grade, or QTc
interval >470 msec.


9. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal
medical therapy)


10. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg po
daily for deep vein thrombosis prophylaxis is allowed).


11. Known HIV infection


12. Pregnancy or breastfeeding. Female patients who are pregnant or nursing, female of
child-bearing potential who is unwilling to use adequate contraception to prevent
pregnancy during the program. All female patients with reproductive potential must
have a negative pregnancy test (serum or urine) prior to study entry.


13. Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that would impart, in the judgment of the investigator, excess risk
associated with study participation or study drug during administration, or which, in
the judgment of the investigator, would make the patient inappropriate for entry into
this study.

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Advanced Information
Descriptive Information
Brief Title  ICMJE Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib
Official Title  ICMJE Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib in Patients With HER2-negative Stage II/III Breast Cancer
Brief Summary

Phase Ib part:

? Primary objective: To demonstrate the recommended dose of the combination of paclitaxel, gemcitabine, and sunitinib (sutene®) (PGS) as preoperative chemotherapy in patients with HER2-negative operable breast cancer

  • Secondary objective:

    1. To demonstrate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this regimen
    2. To determine the safety profile

      Phase II part

  • Primary objective:

To evaluate the pathologic complete response rate (pCR) to preoperative administration of PGS

? Secondary objective:

  1. To assess breast conserving rate after preoperative PGS
  2. To evaluate clinical response rate, disease free survival (DFS), and overall survival (OS)
  3. To assess the safety profiles of PGS
Detailed Description

Unlike adjuvant chemotherapy, primary (preoperative) chemotherapy will shrink tumor and allow more patients to become candidates for conservative surgery and avoid mastectomy. It also is an in vivo chemosensitivity test and the result is a predictive marker for clinical outcomes.

Paclitaxel has been shown to be an effective agent in the treatment of breast cancer. Gemcitabine is a cytosine arabinoside prodrug analog and shows response rates of 15% to 46% as a single agent with very low toxicity. The combination of paclitaxel and gemcitabine (PG) resulted in improvement in objective response rate, time to progression and overall survival compared to paclitaxel monotherapy in patients with metastatic breast cancer. In addition, primary chemotherapies with PG and PGH (PG + trastuzumab) showed significant activity and very low toxicity in phase II studies performed at National Cancer Center, Korea (ASCO 2007 and SABCS 2008, respectively).

Sunitinib is an oral small molecular tyrosine kinase inhibitor that exhibits potent anti-angiogenic and antitumor activity. Sunitinib is a rationally designed small molecule that inhibits members of the split-kinase domain family of receptor tyrosine kinases (RTKs) including the vascular endothelial growth factors (VEGFs) types 1, 2, and 3, platelet-derived growth factor receptor (PDGFR)-?, and -?, stem cell factor receptor (KIT), colony stimulating factor 1 receptor (CSF-1R), Fms-like tyrosine kinase (FLT-3), and glial cell line-derived neurotrophic factor receptor (RET). Inhibition of these RTKs blocks signal transduction, thereby affecting many of the process involved in tumor growth, progression, metastasis, and angiogenesis. Angiogenesis plays a vital role in the growth and metastasis of solid tumors. Preclinical and indirect clinical evidence has accumulated to support the role of neo-angiogenesis in the pathogenesis and progression of breast cancer. Breast cancer neo-vascularization, as measured by an increase in microvessel density, is correlated with the extent of disease and is associated with vascular invasion of the tumor, a prerequisite for blood-borne metastasis. VEGFR signaling is also implicated in the pathobiology of breast cancer. Breast cancer patients exhibit high levels of circulating VEGF and other RTKs are very likely implicated in breast cancer pathogenesis.

Interestingly, a phase II study (Study A6181002) of single-agent sunitinib (50 mg/d on schedule 4/2) in breast cancer patients with anthracycline- and taxane-refractory metastatic disease revealed a response rate of approximately 14% in 51 assessable patients, leading to additional accrual.

When sunitinib is combined with paclitaxel, significant activity was noticed with tolerable toxicity profile in a phase I trial (SABCS 2007). Based on this trial, phase III trial of paclitaxel and sunitinib is ongoing. In addition, phase I trials of gemcitabine and sunitinib combination are ongoing.

Based both on the significant activity of PG combination regimens in the neoadjuvant and metastatic setting and on the phase I trials of combination regimens with sunitinib-paclitaxel and sunitinib-gemcitabine, we plan to conduct a phase IB/II study of primary chemotherapy with sunitinib, paclitaxel and gemcitabine in patients with HER2-negative stage II/III breast cancer. The goal of this phase IB/II study is to define the recommended dose and maximum tolerable dose of paclitaxel and gemcitabine in combination with sunitinib, and explore the activity of this combination as preoperative chemotherapy in patients with HER2-negative operable breast cancer.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE Drug: Paclitaxel,Gemcitabine,Sunitinib

To determine the MTD, only DLT occurring during the first cycle of treatment will be considered. And MTD is defined as the dose level at which at least one-third of patients experience a DLT during their first treatment course. The recommended dose level for the subsequent phase II study is defined as the preceding dose level before the MTD is attained.

If MTD is not reached, the recommended initial dose of the phase II part will be at the dose of paclitaxel 80 mg/m2 and gemcitabine 1200 mg/m2 (days 1, 8) with sunitinib 37.5 mg qd D2-D15.

Other Name: PGS
Study Arms  ICMJE Experimental: Paclitaxel, Gemcitabine, Sunitinib
Paclitaxel, Gemcitabine, Sunitinib
Intervention: Drug: Paclitaxel,Gemcitabine,Sunitinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 1, 2012)
15
Original Estimated Enrollment  ICMJE
 (submitted: February 17, 2010)
58
Actual Study Completion Date  ICMJE November 2010
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age ? 18 years
  2. ECOG performance status 0-2
  3. Histologically confirmed and newly diagnosed breast cancer
  4. Documented HER2/neu non-overexpressing or non-amplified disease

    • 0-1+ by HER2 IHC or
    • HER2 gene non-amplification by HER2 FISH
  5. Clinical stage II or III operable breast cancer
  6. Axillary node positivity determined by cytology
  7. No prior hormonal, chemotherapy or radiotherapy is allowed
  8. No breast operation other than biopsy to make diagnosis is allowed
  9. Adequate hematologic, hepatic and renal function

    • Absolute neutrophil count ? 1,500/?L
    • Hemoglobin ? 10.0 g/dL
    • Platelet ? 100,000/?L
    • AST/ALT ? 2 X UNL (upper limit of normal)
    • Total bilirubin ? 1.5 mg/dL
    • Alkaline phosphatase ? 2 X UNL
    • Serum creatinine ? 1.5 mg/dL
  10. Adequate cardiac function LVEF ? 50% and within the institutional range of normal as measured by echocardiogram or MUGA scan within 4 weeks of enrollment
  11. Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to registration
  12. Normal mental function to understand and sign the consent

Exclusion Criteria:

  1. Patients with metastatic breast cancer
  2. Patients who received hormonal, chemotherapy or radiotherapy for breast cancer
  3. Patients who underwent surgery for breast cancer
  4. Patients with T2N0, or inflammatory (T4d) breast cancer
  5. Patients who have history of cancer other than in situ uterine cervix cancer or nonmelanotic skin cancer
  6. Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)
  7. Any of the following within the 12 months prior to starting study treatment

    • severe, unstable angina
    • Myocardial infarction
    • Uncontrolled or symptomatic congestive heart failure
    • coronary/peripheral artery bypass graft
    • cerebrovascular accident including transient ischemic attack
    • pulmonary embolism
  8. Ongoing cardiac dysrhythmias of grade ?2, atrial fibrillation of any grade, or QTc interval >470 msec.
  9. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)
  10. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg po daily for deep vein thrombosis prophylaxis is allowed).
  11. Known HIV infection
  12. Pregnancy or breastfeeding. Female patients who are pregnant or nursing, female of child-bearing potential who is unwilling to use adequate contraception to prevent pregnancy during the program. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to study entry.
  13. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug during administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Sex/Gender  ICMJE
Sexes Eligible for Study:Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01070706
Other Study ID Numbers  ICMJE NCCCTS-08-369
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jungsil Ro, National Cancer Center, Korea
Study Sponsor  ICMJE Jungsil Ro
Collaborators  ICMJE
  • Pfizer
  • HK inno.N Corporation
Investigators  ICMJE
Principal Investigator:Jungsil RoChief, Center for Breast Cancer, National Cancer Center, Korea
PRS Account National Cancer Center, Korea
Verification Date January 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP