|Phase I||Biomarker/Laboratory analysis, Treatment||Active||18 and over||NCI||110160|
- 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.
- To study the effectiveness of SS1P plus two drugs that suppress the immune system to treat malignant mesothelioma.
- Individuals at least 18 years of age who have malignant mesothelioma in the chest or abdomen.
- 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.
Further Study Information
Platinum-based chemotherapy is the standard of care for advanced unresectable malignant mesothelioma. New options for treatment are necessary in patients with advanced disease that have progressed on platinum-based therapy. Mesothelin is a cell surface glycoprotein present on normal mesothelial cells that is highly expressed in many human cancers including lung adenocarcinoma. SS1 (dsFv) PE38 is a recombinant anti-mesothelin immunotoxin that has undergone phase I testing and has been evaluated in combination with pemetrexed and cisplatin for treatment of malignant pleural mesothelioma. SS1 (dsFv)PE38 is highly immunogenic and the majority of patients develop antibodies to it at end of one cycle. Pre-clinical studies demonstrate that SS1(dsFv)PE38 may be administered multiple times in combination with an immune-depleting regimen consisting of pentostatin and cyclophosphamide.
-To assess the safety, tolerability, and feasibility of a conditioning regimen of pentostatin and
cyclophosphamide in combination with SS1(dsFv)PE38
- To monitor antibody formation to SS1(dsFv)PE38 and to assess the impact of the conditioning regimen on the formation of these antibodies
Phase 2 Objectivies:
- To evaluate objective tumor response in subjects with pleural and with peritoneal mesothelioma using Regimen A.
- Patients with histologically confirmed malignant pleural or peritoneal mesothelioma with epithelial or biphasic tumors having less than a 50% sarcomatoid component who have previously been treated on at least one platinum-containing chemotherapy regimen with progressive disease documented prior to study entry
- Measurable disease by modified RECIST criteria for pleural mesothelioma or by RECIST criteria for peritoneal mesothelioma
- Adequate renal, hepatic and hematopoietic function
- No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of therapy
- During the pilot phase of this study, the first eleven patients enrolled in this study received a conditioning regimen of pentostatin on days 1, 5 and 9 of the first cycle and day 1 of subsequent cycles in combination with cyclophosphamide on days 1 through 12 of the first cycle and days 1 through 4 of subsequent cycles (Regimen A) while the next 8 patients received conditioning regimen of pentostatin on days 1, 5, 9, 13 and 17 of thefirst cycle and day 1 and 5 of subsequent cycles in combination with cyclophosphamide on days 1 through 20 of the first cycle and days 1 through 8 of subsequent cycles (Regimen B). SS1P was administered every other day for six days (3 doses) beginning on the day after the last pentostatin dose in each cycle for both regimens.
- In the phase 2 portion of the study, a two-stage Minimax phase II trial design will be used to enroll up to 16 evaluable subjects with pleural mesothelioma (cohort 1) and up to 10 evaluable subjects with peritoneal mesothelioma (cohort 2) who will receive treatment on Regimen A
- Treatment cycles will be repeated for up to four cycles if patients do not develop neutralizing antibodies, which will be assessed by a biological assay 14 and 20 days (+/- 2 days) following the first dose of SS1P in each cycle (corresponding to Days 24 and 30 of Cycle 1, and Days 16 and 22 of Cycles 2 through 4)
- Toxicity will be assessed by the CTEP Version 4.0 of CTCAE
- Tumor response assessments will be performed at the end of 2 cycles and at the end of treatment
- Tumor biopsies will be performed before treatment, after 2 cycles, and after the last cycle or at follow-up.
1. Subjects must have histologically confirmed epithelial or biphasic mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a greater than or equal to 50 percent sarcomatoid component will be excluded. The diagnosis will be confirmed by the Laboratory of Pathology / CCR / NCI.
2. Patients must have had at least one prior chemotherapy regimen, with the 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.
3. 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.
4. 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.
5. Age greater than or equal to 18 years. Since mesothelioma is extremely rare in children, they are excluded from this study.
6. Life expectancy of greater than 3 months.
7. Performance status (ECOG) less than or equal to 1 (Appendix A).
8. Patients must have adequate organ and marrow function (as defined below).
- leukocytes greater than or equal to 3,000/mm(3)
- absolute neutrophil count greater than or equal to 1,500/mm(3)
- hemoglobin greater than or equal to 9 g/dL
- platelets greater than or equal to 90,000/ mm(3)
- total bilirubin less than or equal to 1.5 times institutional upper limit of normal (ULN)
- AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional ULN (5 times if LFT elevations due to liver metastases)
- creatinine less than or equal to 1.5 times institutional ULN
- 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 greater than or equal to 9 g/Dl.
9. 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.
10. Ability to comply with intravenous administration schedule, and the ability to understand and the willingness to sign a written informed consent document.
1. 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.
2. Uncontrolled medical illness including, but not limited to, ongoing or uncontrolled, symptomatic congestive heart failure (AHA Class II or worse), uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
3. 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.
4. Patients with Hepatitis B and C will be excluded.
5. Serum neutralization antibody assay shows greater than or equal to 75 percent neutralization of the SS1 (dsFv) PE38 activity at 200 ng/ml.
6. Patients may not be receiving any other investigational agents.
7. 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.
8. Prior treatment with drugs of the immunotoxin class.
9. Patients with tumor amenable to potentially curative therapy as assessed by the investigator. In patients with peritoneal mesothelioma who have had no prior surgery, a surgical consultation will be obtained to see if the patient is a candidate for debulking surgery.
10. 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.
11. History of allergic reactions attributed to compounds of similar chemical or biologic composition to SS1(dsFv)PE38.
Trial Lead Organizations/Sponsors
National Cancer Institute
|Raffit Hassan, M.D.||Principal Investigator|
|Yvonne D Mallory, R.N.||Ph: (301) 402-0255|
|NIH - Warren Grant Magnuson Clinical Center|
|For more information at the NIH Clinical Center contact National Cancer Institute Referral Office||Ph: (888) NCI-1937|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01362790
ClinicalTrials.gov processed this data on February 19, 2014
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