Pemetrexed Disodium and Cisplatin With or Without Cediranib Maleate in Treating Patients With Malignant Pleural Mesothelioma

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) and the recommended phase II dose of
cediranib maleate (cediranib) in combination with cisplatin and pemetrexed disodium
(pemetrexed). (Phase I) II. To assess the safety and toxicity of the regimen. (Phase I) III.
To assess whether cisplatin/pemetrexed plus cediranib as compared to cisplatin/pemetrexed
plus placebo improves progression-free survival in patients with malignant pleural
mesothelioma. (Phase II) IV. To compare overall survival in patients treated with
cisplatin/pemetrexed plus cediranib to those treated with cisplatin/pemetrexed plus placebo.
(Phase II) V. To assess the safety and toxicity profile of the regimen. (Phase II) VI. To
assess response rate (confirmed and unconfirmed, complete and partial responses) and disease
control rate (response or stable disease) in the subset of patients with measurable disease
by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. (Phase II) VII. To assess
response rate and disease control rate using modified RECIST criteria for pleural tumors in
the subset of patients with measurable disease by modified RECIST criteria for pleural
tumors. (Phase II) VIII. To assess the rate of agreement between local and central pathology
review of mesothelioma and its histologic subtypes. (Phase II) IX. To collect specimens for
banking for use in future research studies. (Phase II)

OUTLINE: This is a phase I dose-escalation study of cediranib maleate followed by a phase II
study.

PHASE I (CLOSED): Patients receive pemetrexed disodium intravenously (IV) over 10 minutes and
cisplatin IV over 2 hours on day 1 and cediranib maleate orally (PO) once daily (QD) on days
1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or
unacceptable toxicity. Patients then receive cediranib maleate alone PO QD in the absence of
disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours
on day 1 and cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for 6
courses in the absence of disease progression or unacceptable toxicity. Patients then receive
cediranib maleate alone PO QD in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pemetrexed disodium and cisplatin as in arm I and placebo PO QD on
days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity. Patients then receive placebo alone PO QD in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years and
then at 3 years.

Inclusion Criteria:

- Patient must have histologically or cytologically confirmed diagnosis of malignant
pleural mesothelioma; surgical resection must not be planned

- Patients must have measurable or non-measurable disease by both RECIST and modified
RECIST criteria for pleural tumors as documented by computed tomography (CT) scan;
examinations for assessment of measurable disease must have been completed within 28
days prior to registration; examinations for assessment of non-measurable disease must
have been performed within 42 days prior to registration; all disease must be assessed
and documented on the RECIST 1.1 and Modified RECIST Baseline Tumor Assessment Form

- Patients must not have received any prior systemic therapy (chemotherapy or other
biologic therapy) for their unresectable malignant pleural mesothelioma; prior
systemic chemotherapy or biologic therapy is allowed as neoadjuvant or adjuvant
treatment, disease has now recurred, and all systemic treatment was completed > 6
months prior registration; prior therapy must not have included cediranib

- Patients may have received prior surgery (e.g., pleurectomy, pleurodeisis) provided at
least 28 days have elapsed since surgery (thoracic or other major surgeries) and
patients have recovered from all associated toxicities at the time of registration;
there must be no anticipated need for major surgical procedures during protocol
treatment

- Patients may have received prior radiation therapy provided at least 28 days have
elapsed since the last treatment and patients have recovered from all associated
toxicities at the time of registration

- Institutions must seek additional patient consent for the banking and future use of
specimens

- Patient must have Zubrod performance status 0-2

- Absolute neutrophil count >= 1,500 mcl

- Platelets >= 100,000/ml

- Hemoglobin >= 9.0 g/dl (may be reached by transfusion)

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

- Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate
transaminase (SGPT) =< 2.5 x ULN (if liver metastases are present, SGOT or SGPT must
be =< 5.0 x IULN)

- Serum creatinine =< 1.5 x IULN

- Calculated creatinine clearance >= 60 mL/min

- Urine protein must be screened by urine analysis within 28 days prior to registration;
patient must not have greater than +1 proteinuria on two consecutive dipsticks taken
no less than 7 days apart; however, if the first urinalysis shows no protein, then a
repeat urinalysis is not required

- Patient must have an electrocardiogram (ECG) performed within 42 days prior to
registration; patient must not have mean corrected QT (QTc) > 500 msec (with Bazett's
correction) in screening electrocardiogram, or other significant ECG abnormality, New
York Heart Association (NYHA) classification III or IV; patient must not require
concurrent use of drugs or biologics with proarrhythmic potential

- Patient must not be receiving any medication that may markedly affect renal function
(e.g., vancomycin, amphotericin, pentamidine)

- Patient must not have had clinically significant hemoptysis, defined as greater than 1
tablespoon of bright red blood, within one year prior to registration; although
hemoptysis has not been associated with cediranib, it may be a class effect for
anti-angiogenic agents and therefore a risk factor for this experimental agent

- Patient must be able to swallow oral medications

- Patients must not have known human immunodeficiency virus (HIV) infection

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- Patient must have no plans to receive concurrent chemotherapy, hormonal therapy,
radiotherapy, immunotherapy or any other type of therapy for treatment of cancer while
on this protocol treatment

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for five years