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A Pilot Study of Pentostatin Plus Cyclophosphamide Immune Depletion to Decrease Immunogenicity of SS1P in Patients With Mesothelioma


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Mesothelioma

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Trial Information

A Pilot Study of Pentostatin Plus Cyclophosphamide Immune Depletion to Decrease Immunogenicity of SS1P in Patients With Mesothelioma


BACKGROUND:

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.

OBJECTIVES:

Primary Objectives:

-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

ELIGIBILITY:

- 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

DESIGN:

- 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)

- The next 10 evaluable patients will receive conditioning regimen of pentostatin on days
1, 5, 9, 13 and 17 of the first 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)

- Patients receiving Regimen A are treated with SS1(dsFv)PE38 on days 10, 12 and 14 of
the first cycle and days 2, 4, and 6 of each subsequent cycle

- Patients receiving regimen B will be treated with SS1(dsFv)PE38 on days 18, 20 and 22
of the first cycle and days 6, 8, and 10 of each subsequent cycle

- In regimen A, the first cycle consisted of 30 days, and each subsequent cycle consisted
of 21 days. Treatment cycles will be repeated for up to six 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 6)

- In regimen B, the first cycle will consist of 38 days, and each subsequent cycle will
consist of 25 days. SS1(dsFv)PE38 will be given at a dose of 35 mcg/kg. Treatment
cycles will be repeated for up to six 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 32 and 38 of
Cycle 1, and Days 20 and 26 of Cycles 2 through 6)

- 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.

Inclusion Criteria


-INCLUSION CRITERIA:

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

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 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.

EXCLUSION CRITERIA:

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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determining safety, tolerability, and feasibility of a conditioning regimen of pentostatin and cyclophosphamide in combination with SS1(dsFv)PE38

Principal Investigator

Raffit Hassan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110160

NCT ID:

NCT01362790

Start Date:

May 2011

Completion Date:

Related Keywords:

  • Mesothelioma
  • Immune Therapy
  • Immunotoxin
  • T-Cell Depletion
  • Mesothelioma
  • Mesothelioma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892