PD0332991/Paclitaxel in Advanced Breast Cancer

Study Description

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Brief Summary:

This study is a phase I, single arm, open-label trial of PD0332991 in combination with Paclitaxel in patients with Rb-expressing metastatic breast cancer. Up to 20 patients are anticipated to be enrolled to reach the MTD of PD0332991 in combination with Paclitaxel. Once the MTD is established, an additional expanded cohort of 10 patients will be enrolled at that dose to establish the RP2D, obtain additional safety data and perform exploratory biomarker studies.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: PD0332991; Drug: Paclitaxel	Phase 1

Detailed Description:

This study is a phase I, single arm, open-label trial of PD0332991 in combination with paclitaxel in patients with Rb-expressing metastatic breast cancer. Patients will be treated as shown in the schema below. Up to 20 patients are anticipated to be enrolled to reach the MTD of PD0332991 in combination with Paclitaxel. Once the MTD is established, an additional expanded cohort of 10 patients will be enrolled at that dose to estalish the RP2D, obtain additional safety data and perform exploratory biomarker studies. The primary endpoint will be assessed after one cycle of therapy. Patients will remain on study until dose limiting toxicity, disease progression or physician/patient discretion. Safety assessment will continue for the durationof patient participation.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	20 participants
Intervention Model:	Single Group Assignment
Primary Purpose:	Treatment
Official Title:	A Phase 1 Trial of PD0332991 and Paclitaxel in Patients With Rb-Expressing Advanced Breast Cancer
Actual Study Start Date :	March 2011
Actual Primary Completion Date :	April 2017

Arms and Interventions

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Outcome Measures

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Primary Outcome Measures :

1. To Determine the Adverse Events of PD0332991
   To determine the maximally-tolerated dose and safety of PD0332991 in combination with a fixed, weekly dose of Paclitaxel of 80 mg/m2 and to characterize the safety of the combination during the first three cycles of therapy.

Secondary Outcome Measures :

1. Maximally Tolerated Dose in an expanded Cohort of Breast Cancer Patients
   To explore the activity of the combination at the MTD in an expanded cohort of breast cancer patients.
2. To explore the relationship between selected biomarkers and efficacy, tolerability and safety outcomes
   To explore the relationship between selected biomarkers and efficacy, tolerability and safety outcomes

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patient must have histologically or cytologically-confirmed metastatic breast cancer. Any ER, PR or Her2 status is allowed.
• Tumor must express Retinoblastoma (Rb) protein, as defined as any measureable staining by immunohistochemistry
• Male or female and > 18 years of age on the day of signing informed consent.
• Patient must have received < prior cytotoxic regimens for metastatic breast cancer. This does not include cytoxic regimens used in the adjuvant setting.
• Performance status of 0-1 on the ECOG Performance Scale and life expectancy > 3 months.
• patient on the dose-escalation portion of the trial must have evaluable disease, defined as either measurable (by RECIST) or non-measurable disease (e.g. bone mets, pleural effusion or lymphangitic spread). Measurable disease is required for patients in the expanded RP2D cohort.
• The subject must have adequate organ function, defined as follows:

Bilirubin < 1.5 x UNL or calculated creatinine clearance > 60 mL/min, and for subjects without liver metastases: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN

• For subjects without extensive bone metastases: alkaline phosphatase levels < 2.5 x ULN.
• For subjects with extensive bone metastases: alkaline phosphatase levels < 5 x ULN.
• The subject must have adequate marrow function, defined as follows
• Absolute neutrophil count (ANC) >1500/mm
• Platelets > 100,000/mm
• Hemoglobin > 9 g/dL
• Female patient of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication and agree to the use of effective methods of contraception while on study.
• Patient must be capable of, and must voluntarily agree to participate by giving written informed consent.
• Patient must be able to swallow capsules and has no surgical or anatomical condition that will preclude the patient from swallowing and absorbing oral medicatios on an ongoing basis.
• Prior taxane therapy in the adjuvant or metastatic setting is allowed.
• Concomitant use of biophosphonates is allowed.
• Patients with stable, treated CNS disease are eligible.

Exclusion Criteria:

• Patient who has had chemotherapy, radiotherapy or hormonal therapy within 3 weeks (6 weeks for nitrosoureas, mitomycin C or bevacizumab), or who has not recovered from the adverse events due to previous agents administered more than 4 weeks prior to Study Day 1. If the patient has residual toxicity from prior treatment, toxicity must be < Grade 1.
• patients less than 4 weeks post major surgical procedure (all surgical wounds must be fully healed). For the purpose of this criterion, a major surgical procedure is defined as one requiring the administration of general anesthesia.
• Patient has known active CNS metastases and/or carcinomatous meningitis. However, patients with CNS metastases (including brain metastases) who have completed a course of radiotherapy are eligible for the study provided they are clinically stable. Oral corticosteroids for control of CNS symptoms are allowed.
• Patient has known hypersensitivity to the components of study drug or its analogs.
• The subject has uncontrolled intercurrent illness including, but not limited to Ongoing or active infection
• Diabetes mellitus
• Hypertension
• Symptomatic congestive heart failure, unstable angina pectoris, stroke or myocardial infarction within 3 months.
• Patient has baseline neuropathy of > grade 2
• Patients who have known allergic reactions to Paclitaxel or IV Contrast Dye despite standard prophylaxis.
• The subject is pregnant or breastfeeding
• The subject is known to be positive for the human immunodeficiency virus (HIV). Note: baseline HIV screening is not required.
• The subject is unable eor unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

Contacts and Locations

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Locations

United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

Abramson Cancer Center of the University of Pennsylvania

More Information

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Responsible Party:	Abramson Cancer Center of the University of Pennsylvania
ClinicalTrials.gov Identifier:	NCT01320592 History of Changes
Other Study ID Numbers:	UPCC 02111
First Posted:	March 22, 2011
Last Update Posted:	August 28, 2018
Last Verified:	August 2018

Keywords provided by Abramson Cancer Center of the University of Pennsylvania:

Patient must have histologically or cytologically-confirmed metastatic; breast cancer; Any ER, PR or Her2 status is allowed.; Tumor must express Retinoblastoma (Rb) protein, defined as; any measurable staining by immunohistochemistry on the invasive tumor component	<3 prior cyttoxic chemotherapy regimens for metastatic disease.; Performance status of 0-1 on the ECOG Performance Scale and life expectancy > 3 months.; Patient must have evaluable disease. Measureable disease is not required.; The subject has adequate organ function

Additional relevant MeSH terms:

Palbociclib; Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Albumin-Bound Paclitaxel	Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Protein Kinase Inhibitors; Enzyme Inhibitors