Neuroendocrine Carcinoma
Conditions
Keywords
advanced neuroendocrine, Gastrointestinal, Bevacizumab, Avastin, Pertuzumab, Omnitarg, 2C4, Sandostatin, Octreotide
Brief summary
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.
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.
Interventions
DRUGBevacizumab
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.
DRUGPertuzumab
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.
DRUGSandostatin 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.
Sponsors
Genentech, Inc.
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 18 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Define Toxicity and Safety | 18 months | 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 |
| Progression-Free Survival (PFS) | 18 months | 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. |
| Overall Survival (OS) | 18 months | The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death |
| Disease Control Rate | 18 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Patients 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.
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.
Sandostatin LAR® Depot: 30 mg will be given every 28 days by IM injection. | 43 |
| Total | 43 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 62 years |
| Region of Enrollment United States | 43 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 42 / 43 |
| serious Total, serious adverse events | 6 / 43 |
Outcome results
Primary
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.
Time frame: 18 months
Population: Includes all patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Typical Carcinoid | Objective Response Rate (ORR) | 16 percentage of participants |
| Pancreatic Islet Cell | Objective Response Rate (ORR) | 18 percentage of participants |
| All Patients | Objective Response Rate (ORR) | 16 percentage of participants |
Secondary
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
Time frame: 18 months
Population: All patients on study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Typical Carcinoid | Define Toxicity and Safety | Hypertension | 11 participants |
| Typical Carcinoid | Define Toxicity and Safety | Pain | 5 participants |
| Typical Carcinoid | Define Toxicity and Safety | Left ventricular systolic dysfunction | 5 participants |
| Typical Carcinoid | Define Toxicity and Safety | Diarrhea | 3 participants |
| Typical Carcinoid | Define Toxicity and Safety | Anemia | 1 participants |
| Typical Carcinoid | Define Toxicity and Safety | Leukopenia | 1 participants |
Secondary
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.
Time frame: 18 months
Population: Includes all patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Typical Carcinoid | Disease Control Rate | 72 percentage of participants |
| Pancreatic Islet Cell | Disease Control Rate | 91 percentage of participants |
| All Patients | Disease Control Rate | 77 percentage of participants |
Secondary
Overall Survival (OS)
The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death
Time frame: 18 months
Population: Includes all patients (patients in both the typical carcinoid and pancreatic islet cell groups received the same treatment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Typical Carcinoid | Overall Survival (OS) | NA months |
| Pancreatic Islet Cell | Overall Survival (OS) | 26.4 months |
Secondary
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.
Time frame: 18 months
Population: Includes all patients (patients in both the typical carcinoid and pancreatic islet cell groups received the same treatment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Typical Carcinoid | Progression-Free Survival (PFS) | 11.96 months |
| Pancreatic Islet Cell | Progression-Free Survival (PFS) | 5.49 months |