SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

BACKGROUND:

Mesothelin is a cell surface glycoprotein present on normal mesothelial cells that is highly
expressed in many human cancers including mesothelioma, lung and pancreatic 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:

Mesothelioma Pilot Objective

-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

Mesothelioma Positive Cancers Dose De-escalation Pilot Objective

-To determine the safety profile and recommended phase 2 dose of SS1P (dsFv)PE38 in

drug lot FIL129J01 using dosing regimen A in patients with mesothelioma, lung and pancreatic
adenocarcinoma

Phase 2 and Lung and Pancreatic Adenocarcinoma Expansion Pilot Objective

-To evaluate objective tumor response in subjects with pleural mesothelioma, peritoneal

mesothelioma, lung and pancreatic adenocarcinoma using Regimen A

ELIGIBILITY:

- Patients with one of the following histologically confirmed malignancies:

- 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

- advanced (Stage IIIB/IV) lung adenocarcinoma who have had at least one prior
chemotherapy for advanced disease. Patients who received an approved targeted
therapy as first-line treatment should have also received chemotherapy prior to
study entry.

- recurrent, locally advanced unresectable or metastatic adenocarcinoma of the
pancreas.

- Measurable disease by modified RECIST criteria for pleural mesothelioma or by RECIST
criteria for peritoneal mesothelioma, lung adenocarcinoma and pancreatic adenocarcinoma

- Adequate renal, hepatic and hematopoietic function

- No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of
therapy

DESIGN:

-During the mesothelioma pilot phase of this study, the first eleven mesothelioma 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 mesothelioma patients received 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). 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 mesothelin positive cancers dose de-escalation pilot study, a maximum of 12
patients with mesothelioma or lung or pancreatic adenocarcinoma will be enrolled in a
3+3 design to test up to 2 decreasing dose levels of SS1P administered in combination
with cyclophosphamide and pentostatin on the Regimen A schedule for safety.

- In the phase 2 mesothelioma and pancreatic and lung adenocarcinoma pilot expansion
portions 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), up to 10 evaluable
subjects with peritoneal mesothelioma (cohort 2), up to 10 patients with lung
adenocarcinoma (cohort 3)and up to 10 evaluable subjects with pancreatic adenocarcinoma
(cohort 4) 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.

- 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 / CCR / NCI.

- Patients must have had at least one prior chemotherapy regimen, with the FDAapproved
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
[platinumcontaining chemotherapy or one of the approved targeted therapies (an
approved EGFR 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 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 (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/mm3

- absolute neutrophil count less than or equal to 1,500/mm3

- hemoglobin less than or equal to 9 g/dL

- platelets less than or equal to 90,000/ mm3

- total bilirubin See guidelines for individual cohorts in sections 3.1.1.3,
3.1.2.4 and 3.1.3.3

- AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional ULN (5x if 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 m2 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 (AHA Class II or worse), uncontrolled
hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.

- 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.