Combination of Bevacizumab, Pertuzumab, and Sandostatin for Adv. Neuroendocrine Cancers

Phase II Study of the Combination of Bevacizumab, Pertuzumab, and Sandostatin for Patients With Advanced Neuroendocrine Cancers.

The purpose of this Phase II trial will be to define the activity of a VEGF inhibitor

bevacizumab, HER1/HER2 inhibitor pertuzumab, and sandostatin for patients with

advanced neuroendocrine cancers. In particular, the efficacy of bevacizumab and

pertuzumab treatment is of great interest. The primary endpoint of this trial will be

response rate. Toxicity and progression-free survival will be obtained and evaluated.

Study Overview

• Status: Completed
• Conditions: Neuroendocrine Carcinoma
• Intervention / Treatment: Drug: Bevacizumab; Drug: Pertuzumab; Drug: Sandostatin LAR® Depot

Detailed Description

• To determine overall response rate of patients with low grade neuroendocrine cancer when treated with the combination of bevacizumab, pertuzumab and sandostatin LAR®.
• To determine the disease control rate (objective response + stable disease), time to treatment progression, progression-free survival, and overall survival in patients with advanced low grade neuroendocrine cancer when treated with bevacizumab, pertuzumab and Sandostatin LAR® treatment.
• To define the toxicity and safety of the combination of bevacizumab, pertuzumab and Sandostatin LAR® when used in patients with advanced low grade neuroendocrine cancer.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
  • Georgia
    • Augusta, Georgia, United States, 30901
      • Medical Oncology Associates of Augusta
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Baptist Medical Center East
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Grand Rapids Oncology Program
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Hematology-Oncology Associates of Northern NJ
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care, Inc
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology Associates

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. Patients with biopsy-proven advanced, unresectable or metastatic, well-differentiated (or low-grade) neuroendocrine carcinoma, including typical carcinoid, pancreatic islet cell and other well-differentiated neuroendocrine carcinomas.
2. Patients with documented evidence of disease progression.
3. Patients currently receiving or previously treated with single agent Sandostatin LAR® are eligible.

4. Patients must have >=1 unidimensional measurable lesion definable by

   MRI or CT scan. Disease must be measurable per RECIST version 1.1 criteria.

5. Left Ventricular Ejection Fraction (LVEF) >=50% as determined by either ECHO or MUGA <=6 weeks prior to study entry.
6. An ECOG Performance Status of 0-2.

7. Laboratory values as follows:

   • ANC >=1500/μL
   • Hgb >=9 g/dL
   • Platelets >=100,000/μL
   • AST/SGOT <=2.5 x ULN or <=5.0 x ULN in patients with liver metastases
   • ALT/SGPT <=2.5 x ULN or <=5.0 x ULN in patients with liver metastases
   • Bilirubin <=1.5 x ULN
   • Creatinine <=2.0 mg/dL or calculated creatinine clearance >=50 mL/min
8. Patients >=18 years of age.
9. Patients must have a life expectancy >12 weeks.
10. Patient must be accessible for treatment and follow-up.
11. Women of childbearing potential must have a negative serum or urine pregnancy test performed <=7 days prior to start of treatment. Women of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately.
12. Patients must be able to understand the nature of the study and give

written informed consent, and comply with study requirements

Exclusion Criteria:

1. Patients with poorly differentiated neuroendocrine carcinoma, highgrade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid, atypical carcinoid, anaplastic carcinoid, and small cell carcinoma are not eligible.
2. Previous treatment with VEGF or EGFR inhibitors.
3. Cytotoxic chemotherapy, immunotherapy or radiotherapy <=4 weeks prior to study entry.
4. History or known presence of central nervous system (CNS) metastases.
5. Patients who have had a major surgical procedure (not including mediastinoscopy), open biopsy, or significant traumatic injury <=4 weeks prior to beginning treatment.
6. Female patients who are pregnant or lactating.
7. History of hypersensitivity to active or inactive excipients of any component of treatment (bevacizumab, sandostatin, and/or pertuzumab).
8. Patients with proteinuria at screening as demonstrated by urine dipstick for proteinuria >=2+ (patients discovered to have >=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection, and must demonstrate <=1 g of protein/24 hours to be eligible).
9. Patients with a serious non-healing wound, active ulcer, or untreated bone fracture.
10. Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
11. Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) <=1 month prior to study enrollment.
12. History of myocardial infarction or unstable angina <=6 months prior to beginning treatment.
13. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and /or diastolic blood pressure >100 mmHg while on antihypertensive medications). Initiation of antihypertensive agents is permitted provided adequate control is documented at least 1 week prior to Day of study treatment.

14. New York Heart Association (NYHA) grade II or greater congestive

    heart failure (CHF).

15. Serious cardiac arrhythmia requiring medication.
16. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) <=6 months prior to Day 1 of treatment.
17. History of stroke or transient ischemic attack <=6 months prior to beginning treatment.
18. Any prior history of hypertensive crisis or hypertensive encephalopathy.
19. History of abdominal fistula or gastrointestinal perforation <=6 months prior to Day 1 of beginning treatment.
20. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
21. Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection.
22. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
23. Use of any non-approved or investigational agent <=28 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
24. Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a DFS >=5 years.
25. Infection requiring IV antibiotics.

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: 1; combination of bevacizumab, pertuzumab, and sandostatin for patients with advanced neuroendocrine cancers

Drug: Bevacizumab; 15 mg/kg IV Day 1. The first dose should be administered over 90 minutes. If no adverse reactions occur after the initial dose, the second dose should be administered over a minimum of 60 minutes. If no adverse reactions occur after the second dose, all subsequent doses should be administered over a minimum of 30 minutes. Bevacizumab will be infused prior to pertuzumab.; Other Names: Avastin; Drug: Pertuzumab; 840 mg IV loading dose infused over 60 minutes. The loading dose is given on Cycle 1, Day 1 or as below. Subsequent doses of pertuzumab are 420 mg IV. If the patient tolerates the initial infusion over 60 minutes, the patient may receive subsequent infusions over 30 minutes. Otherwise, pertuzumab should be infused over 60 minutes. Patients should be observed for 30 minutes after completing the pertuzumab infusion. If a patient misses a dose of pertuzumab for 1 cycle (i.e., 2 sequential cycles or administrations are 6 weeks or more apart), a re-loading dose (840 mg) of pertuzumab should be given. If re-loading pertuzumab is administered, subsequent doses of 420 mg will then be given every 3 weeks, starting 3 weeks later.; Other Names: 2C4; Omnitarg; Drug: Sandostatin LAR® Depot; 30 mg will be given every 28 days by IM injection. The dose of sandostatin may be increased, at the discretion of the treating physician, if necessary to control symptoms related to tumor secretion of vasoactive peptides.; Other Names: Octreotide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The Percentage of Patients Who Experience an Objective Benefit From Treatment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Define Toxicity and Safety	To define the toxicity and safety of the combination of bevacizumab, pertuzumab and Sandostatin LAR® when used in patients with advanced low grade neuroendocrine cancer - defined by grade 3/4, treatment-related toxicity	18 months
Progression-Free Survival (PFS)	The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Worsening of Their Disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	18 months
Overall Survival (OS)	The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death	18 months
Disease Control Rate	The Percentage of Patients Who Experience an Objective Benefit From Treatment or Experience Stable Disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither Sufficient Shrinkage to Qualify For PR, Nor Sufficient Increase to Qualify for Progressive Disease; Disease Control Rate = CR + PR + SD.	18 months

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Genentech, Inc.
• Investigators: Study Chair: Johanna C Bendell, S.B., M.D., SCRI Development Innovations, LLC

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: May 10, 2010
• First Submitted That Met QC Criteria: May 10, 2010
• First Posted (Estimate): May 12, 2010

Study Record Updates

• Last Update Posted (Estimate): February 5, 2016
• Last Update Submitted That Met QC Criteria: January 8, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Bevacizumab; Avastin; advanced neuroendocrine; Gastrointestinal; Pertuzumab; Omnitarg; 2C4; Sandostatin; Octreotide
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Physiological Effects of Drugs; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Octreotide; Pertuzumab
• Other Study ID Numbers: SCRI GI 135

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No