A Trial to Assess the Activity and Safety of Palbociclib in Patients With Well and Moderately Differentiated Metastatic Pancreatic Neuroendocrine Tumors (pNET) (PALBONET)

A Phase II Trial to Assess the Activity and Safety of Palbociclib in Patients With Well and Moderately Differentiated Metastatic Pancreatic Neuroendocrine Tumors (pNET)

A phase II trial to assess the activity and safety of PD0332991 in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET) with overexpression of cell cycle markers (Cdk4 and/or phospho-Rb1 and/or cyclin D1)

Study Overview

• Status: Completed
• Conditions: Pancreatic Neuroendocrine Cancer
• Intervention / Treatment: Drug: Palbociclib

Detailed Description

The purpose of this study is to evaluate the activity and safety of PD0332991 in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET) with overexpression of cell cycle markers (Cdk4 and/or phospho-Rb1 and/or cyclin D1)

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • H. Vall d´Hebron
  • Castelló, Spain, 12002
    • H. Castellon
  • Madrid, Spain
    • H U Ramón y Cajal
  • Madrid, Spain
    • H. 12 Octubre
  • Madrid, Spain
    • H.U.La Paz
  • Sevilla, Spain
    • H.U.Virgen del Rocio
  • Asturias
    • Oviedo, Asturias, Spain
      • H.U.C de Asturias
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain
      • ICO
  • Navarra
    • Pamplona, Navarra, Spain
      • C. H. de Navarra

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically or cytologically proven diagnosis of pancreatic neuroendocrine tumors (pNET) with Ki67 assessment of < or = 20% (well and moderately differentiated) with evidence of unresectable disease or metastatic disease. Locally advanced disease must not be amendable to resection or radiation therapy with curative intent.
2. Overexpression of Cdk4 and/or phospho-Rb1 and/or cyclin D1 in tumor tissue sample from tumor biopsy or prior primary tumor resection (Molecular study will be conducted at CNIO and logistic is described later). Therefore availability of paraffin-embedding tumor tissue sample is needed.
3. Documented progression of the disease by CT scan, MRI, or Octreoscan within 12 months prior to baseline.
4. Previous treatments with chemotherapy, antiangiogenics, or interferon are permitted providing that toxicity has resolved to < grade 1 at study entry and that last treatment was at least 4 weeks prior to baseline assessment. Patients may be treated with somatostatin analogues during the trial. Concomitant interferon treatment is not permitted.
5. Measurable disease as per RECIST. Measurable lesions that have been previously radiated will not be considered target lesions unless increase in size has been observed following completion of radiation therapy.
6. Able to swallow oral compound
7. Male or female, 18 years of age or older.
8. ECOG performance status less than 2.
9. Life expectancy greater than 12 weeks.

10. The definitions of minimum adequacy for organ function required prior to study entry are as follows. In addition, safety precautions provided in the product labeling for the anticipated control arm chemotherapy must be observed.

    • Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 2.5 x upper limit of normal (ULN), or AST and ALT 5 x ULN if liver function abnormalities are due to underlying malignancy
    • Total serum bilirubin 1.5 x ULN
    • Serum albumin 3.0 g/dL
    • Absolute neutrophil count (ANC) 1500/L
    • Platelets 100,000/L
    • Hemoglobin 9.0 g/dL
    • Creatinin clearance < 40 mL/min
11. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Prior chemotherapy regimen or biological treatment for locally advanced or metastatic transitional cell carcinoma of the urinary tract.
2. Prior treatment on Cdk4 inhibitor under clinical trial.
3. Creatinine clearance < 40 ml/min using Cockroft and Gault formula.
4. Major surgery, radiation therapy, or systemic therapy within 3 weeks of study randomization except palliative radiotherapy to non-target metastatic lesions.
5. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
6. Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids taken concurrently or within last 3 months prior to randomization
7. Prior radiation therapy to >25% of the bone marrow.
8. Current treatment on another clinical trial.
9. Uncontrolled brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease. Patients should have completed surgery or radiation therapy for existing brain metastases, should not have documented increase in size over the previous 3 months prior to first dose of treatment on study and should be asymptomatic.
10. Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
11. Any of the following within the 12 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident including transient ischemic attack, or pulmonary embolus.
12. Ongoing cardiac dysrhythmias of NCI CTCAE grade 2, atrial XML File Identifier: 3xAP+CVEwV9UnEoC7xvloFQA/XQ=Page 20/34 fibrillation of any grade, or QTc interval >450 msec for males or >470msec for females.
13. Hypertension that cannot be controlled by medications (>150/100mmHg despite optimal medical therapy)
14. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
15. Known human immunodeficiency virus infection.
16. Pregnancy or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to randomization.
17. 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 administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Palbociclib	Drug: Palbociclib; Palbociclib; Other Names: palbociclib (PD0332991)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Activity of palbociclib (PD0332991) considering objective response rate	20 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival		Patients will be followed until disease progression, estimating around 12months
Time to Tumor Progression		Patients will be followed until disease progression, estimating around 12 months
Duration of response		Patients will be followed until disease progression, estimating around 12 months
Overall Survival		Patients will be followed until death, estimating around 33 months
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 (Safety)	Safety would be measured as Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Patients will be followed until disease progression estimating around 12 months
Positive expression of tumor biomarkers (Cdk4, Cdk6, fosfo-Rb1, D1 cyclin, p53, Ki67)	Percentage of neoplasique cells with positive expression of the following tumor biomarkers Cdk4, Cdk6, fosfo-Rb1, D1 cyclin, p53, Ki67 would be measured at baseline by immunohistochemistry	Positive expression of tumor biomarkers at baseline

Collaborators and Investigators

• Sponsor: Grupo Espanol de Tumores Neuroendocrinos

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: July 8, 2015
• First Submitted That Met QC Criteria: June 17, 2016
• First Posted (Estimate): June 20, 2016

Study Record Updates

• Last Update Posted (Actual): January 23, 2018
• Last Update Submitted That Met QC Criteria: January 18, 2018
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Pancreatic Neoplasms; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Carcinoma, Islet Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Palbociclib
• Other Study ID Numbers: GETNE-1407