Pancreatic Neoplasms Clinical Trial
Official title:
A Pilot/ Phase 2 Study of Pentostatin Plus Cyclophosphamide Immune Depletion to Decrease Immunogenicity of SS1P in Patients With Mesothelioma, Lung Cancer or Pancreatic Cancer
Verified date | June 2019 |
Source | National Institutes of Health Clinical Center (CC) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
Background:
- Malignant mesothelioma is a form of cancer that develops on the protective lining that
covers the body's internal organs. It most often occurs on the lining of the lungs and
chest wall or the lining of the abdomen. There is no known cure for malignant
mesothelioma, so researchers are searching for new ways to treat it.
- Mesothelin is a protein that is found in mesothelioma and other types of cancer cells.
An experimental cancer drug called SS1P is designed to attack cells that have mesothelin
while leaving healthy cells alone. Researchers want to test how effective SS1P is when
it is given with pentostatin and cyclophosphamide. These drugs help suppress the immune
system and may make the SS1P more effective.
Objectives:
- To study the effectiveness of SS1P plus two drugs that suppress the immune system to treat
malignant mesothelioma.
Eligibility:
- Individuals at least 18 years of age who have malignant mesothelioma in the chest or
abdomen.
Design:
- Participants will be screened with a physical exam, medical history, and blood tests.
They will also have imaging studies.
- The first treatment cycle will last 30 days. Up to three 21-day cycles of treatment will
follow.
- In the first cycle, participants will have pentostatin on days 1, 5, and 9. They will
have cyclophosphamide on days 1 through 12. They will have SS1P on days 10, 12, and 14.
- On the next three cycles, participants will have pentostatin on day 1.They will have
cyclophosphamide on days 1 through 4. They will have SS1P on days 2, 4, and 6.
- Participants will have frequent blood tests and other studies. They will receive all
four cycles of treatment as long as there are no severe side effects.
- Participants will have regular followup visits as directed by the study doctors.
Status | Completed |
Enrollment | 55 |
Est. completion date | August 7, 2017 |
Est. primary completion date | August 3, 2016 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 99 Years |
Eligibility |
- INCLUSION CRITERIA: Mesothelioma Cohorts (Cohorts 1 and 2 Only) - Subjects must have histologically confirmed epithelial or biphasic mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a less than or equal to 50% sarcomatoid component will be excluded. The diagnosis will be confirmed by the Laboratory of Pathology / Center for Cancer Research (CCR) / National Cancer Institute (NCI). - Patients must have had at least one prior chemotherapy regimen, with the Food and Drug Administration (FDA) approved regimen of a platinum-based therapy in combination with pemetrexed being preferred unless there was a specific contraindication for an individual patient. There is no limit to the number of prior chemotherapy regimens received. - Total Bilirubin less than or equal to 1.5 X institutional upper limit of normal (ULN) INCLUSION CRITERIA: Lung Adenocarcinoma Cohort (Cohort 3) Only - Subjects must have histologically confirmed advanced (Stage IIIB/IV) lung adenocarcinoma. The diagnosis will be confirmed by the Laboratory of Pathology/CCR/NCI. - Patients must have had at least one prior therapy for advanced disease [platinum containing chemotherapy or one of the approved targeted therapies (an approved estimated glomerular filtration rate (EGFR) tyrosine kinase inhibitor (TKI) for EGFR mutant tumors or crizotinib and ceritinib for ALK translocated tumors)]. There is no limit to the number of prior chemotherapy regimens received. - Mesothelin expression in at least 5% of cells as assessed in archival tumor tissue samples, determined by the immunohistochemistry (IHC) assay performed at Laboratory of Pathology / CCR / NCI. Archival samples must be available for eligibility. - Total Bilirubin less than or equal to 1.5 X institutional upper limit of normal (ULN) INCLUSION CRITERIA: Pancreatic Cancer Cohort (Cohort 4) Only - Subjects with recurrent, locally advanced unresectable or metastatic adenocarcinoma of the pancreas. The diagnosis will be confirmed by the Laboratory of Pathology/CCR/NCI. - Patients must have had at least one prior chemotherapy for advanced disease. There is no limit to the number of prior chemotherapy regimens received. - Total Bilirubin less than or equal to 2 X institutional upper limit of normal (ULN) INCLUSION CRITERIA: All Subjects - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. See Section 11 for the evaluation of measurable disease. - Patients must not have had major surgery, radiation therapy, chemotherapy, biologic therapy (including any investigational agents), or hormonal therapy (other than replacement), within 4 weeks prior to entering the study and must have evidence of stable or progressive disease to be eligible. - Age greater than or equal to 18 years. Since the study diseases are extremely rare in children they are excluded from this study. - Performance status (Eastern Cooperative Oncology Group (ECOG)) less than or equal to 1 - Patients must have adequate organ and marrow function (as defined below). - leukocytes less than or equal to 3,000/mm^3 - absolute neutrophil count less than or equal to 1,500/mm^3 - hemoglobin less than or equal to 9 g/dL - platelets less than or equal to 90,000/ mm^3 - total bilirubin See guidelines for individual cohorts in sections 3.1.1.3, 3.1.2.4 and 3.1.3.3 - Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT))/alanine aminotransferase (ALT)(serum glutamic-pyruvic transaminase (SGPT)) less than or equal to 3 X institutional upper limit of normal (ULN) (5x if liver function test (LFT) elevations due to liver metastases) - creatinine less than or equal to 1.5 X institutional ULN OR --creatinine clearance greater than or equal to 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal, obtained through calculated or measured Creatinine Clearance Patients may be transfused to obtain a hemoglobin of less than or equal to 9 g/Dl. - The effects of SS1(dsFv)PE38, pentostatin, and cyclophosphamide on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) for the duration of study therapy and for 3 months after the last dose of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. While hormonal methods of birth control are effective, we ask that female patients who are participating in the study cease hormonal forms of birth control, as these methods of birth control (birth control pills, injections, or implants) may affect the study drug. Patients must be off hormonal forms of birth control for at least 4 weeks prior to initiating the study. - Ability to comply with intravenous administration schedule, and the ability to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: (All Subjects) - Patients with symptomatic brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 4-6 weeks without steroids may be enrolled at the discretion of the principal investigator. - Uncontrolled medical illness including, but not limited to, ongoing or uncontrolled, symptomatic congestive heart failure (American Heart Association (AHA) Class II or worse), uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. - Human immunodeficiency virus (HIV) positive patients will be excluded due to a theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection. - Patients with Hepatitis B and C will be excluded. - Serum neutralization antibody assay shows greater than or equal to 75% neutralization of the SS1 (dsFv) PE38 activity at 200 ng/ml. - Patients may not be receiving any other investigational agents. - History of another invasive malignancy in the last two years. Adequately treated noninvasive, non-melanoma skin cancers as well as in situ carcinoma of the cervix will be allowed. - Prior treatment with drugs of the immunotoxin class. - Patients with tumor amenable to potentially curative therapy as assessed by the investigator. - Pregnant women are excluded from this study because SS1(dsFv)PE38, pentostatin, and cyclophosphamide have the potential for teratogenic or abortifacient effects. The agents in the trial may also potentially be secreted in milk and therefore breastfeeding women should be excluded. Because of the potential of teratogenic or abortifacient effects women of childbearing potential and men must agree to use adequate contraception (barrier methods) before, during the study and for a period of 3 months after the last dose of the investigational agent. - History of allergic reactions attributed to compounds of similar chemical or biologic composition to SS1(dsFv)PE38. INCLUSION CRITERIA: WOMEN AND MINORITIES -Both men and women and members of all races and ethnic groups are eligible for this trial. Every effort will be made to recruit women and minorities in this study. |
Country | Name | City | State |
---|---|---|---|
United States | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland |
Lead Sponsor | Collaborator |
---|---|
National Cancer Institute (NCI) |
United States,
Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007 Sep 1;13(17):5144-9. — View Citation
Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. — View Citation
Zhang Y, Xiang L, Hassan R, Paik CH, Carrasquillo JA, Jang BS, Le N, Ho M, Pastan I. Synergistic antitumor activity of taxol and immunotoxin SS1P in tumor-bearing mice. Clin Cancer Res. 2006 Aug 1;12(15):4695-701. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Count of Participants SS1P Cycles Received Following Onstudy | Here are the number of participants who had SS1P cycles during cycle 1-6. | Cycles 1-6, up to 180 days | |
Primary | Response Assessment | Response was assessed by the European Organization for Research and Treatment of Cancer (EORTC) modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is complete disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions. Progressive disease (PD) disease is at least a 20% increase in the sum of the LD of target lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | 52 months and 4 days | |
Primary | Count of Participants With SS1P Antibody Formation | Development of antibodies following treatment with SS1P. The goal was to delay development of antibodies to SS1P so a patient could get a second cycle of therapy with SS1P. | On last day of last dosing cycle, end of cycle 1 (day 30) | |
Primary | Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) Who Were Administered SS1P and Pentostatin or Cyclophosphamide | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 64 months and 26 days | |
Primary | Recommended Phase 2 Dose (RP2D) in Drug Lot FIL129J01 | Should any 2 patients within the first 3 to 6 patients experience treatment limiting toxicity requiring cessation of treatment prior to the conclusion of the first cycle, the maximum tolerated dose will have been exceeded and patients will be enrolled to the next lower dose. | Days 1, 3, and 5 of a 21 day cycle | |
Secondary | Overall Survival | The Kaplan-Meier was used to determine the probability of overall survival from on-study date until death or last follow-up (calculated from the date of study entry until the date of analysis). | 36 months | |
Secondary | Progression-free Survival | Defined as the time interval from the start of treatment to documented evidence of disease progression. Progressive disease is assessed by the European Organization for Research and Treatment of Cancer (EORTC) modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum on study LD (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progression). | 36 months | |
Secondary | Duration of Response | DOR is assessed by the European Organization for Research and Treatment of Cancer (EORTC) modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria and is measured from the time measurement criteria is met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to<10mm. partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum on study LD (this includes the baseline sum if that is the smallest on study). | up to 2.5 years |
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