Anti-OX40, Cyclophosphamide (CTX) and Radiation in Patients With Progressive Metastatic Prostate Cancer

A Phase Ib trial design will be employed in patients with metastatic PC who have failed prior
androgen ablation and docetaxel. CTX will be administered also on Day 1. All patients will
receive RT (800 cGy in a single fraction) to up to 3 bone metastatic sites on Day 4 in the
AM. Anti-OX40 at 0.4 mg/kg IV will be given on days 4, 6 and 8. The timing of CTX, RT and
anti-OX40 are based on the pre-clinical models and the observation that the synergies of CTX
and RT are reduced when they are given more than one week after anti-OX40 and are maximized
when given within 3 days of starting anti-OX40. The proposed radiation dose is commonly used
to palliate bone pain in PC and generally will not induce significant cytopenias. The CTX
dose will be escalated in successive cohorts of 3 - 6 patients to assure patient safety. The
dose levels of CTX will be 300, 600 and 900 mg/m2 intravenously in the initial stage of the
study. The range of CTX doses is commonly used in general oncology practice and is not
expected to induce prolonged myelosuppression, although transient cytopenias are likely.
Concurrent CTX and RT has been well-tolerated at much higher dose-intensities than the
investigators are proposing (52-54), thus the investigators are not expecting significant
adverse events from the combination before anti-OX40. As a safety consideration, the
investigators are not giving CTX and RT on the same day as a high proportion of men with
prostate cancer have bone metastases in the pelvis. RT to the pelvis could cause radiation
cystitis that would be exacerbated by the metabolites of CTX (e.g., acrolein) that can
accumulate in the bladder in the 24-36 hours after administration. After the dose-escalation
portion of the trial then up to 20 additional patients can enroll in the study at the maximum
tolerated CTX dose if clinical responses are seen, for a maximum total of 37 patients using a
Simon two-stage design (see Section 10 for details).

The main clinical objective of the trial will be to characterize toxicity and estimate the
response rate of the combination of anti-OX40, CTX and RT. Both radiographic and PSA
responses will be followed. RECIST will be used for radiographic assessment and a significant
PSA response will be defined as a 50% or greater decrease from baseline measured at 3 and 6
weeks after the start of treatment based on the PCWG2 guidelines (55).

Patients will enroll consecutively to each cohort assuming no dose-limiting toxicities. Three
patients will be treated per cohort and if there are no dose-limiting toxicities, then
enrollment to the next cohort can begin. If a dose-limiting toxicity is encountered in the
first three patients in any cohort, then an additional three patients will be enrolled in
that cohort.* This dosing strategy will allow for a three-fold escalation of CTX.

The main hypothesis of this study is that CTX and RT will induce tumor breakdown providing a
source of antigen for self-vaccination and anti-OX40 will amplify CD8-mediated effector
responses across a broad spectrum of prostate cancer antigens resulting in further regression
of prostate cancer. The investigators predict that anti-OX40 will not increase circulating or
intratumoral Treg, and this should help to further augment immune responses.

*For the dose escalation portion of the study, the first 2 patients in any cohort can be
treated on consecutive weeks. If there are no Dose Limiting Toxicities, then the third
patient can begin treatment 28 days after the second patient has completed anti-OX40. If the
third patient has no DLT, then the next cohort can open 28 days after the third patient has
completed anti-OX40. If a DLT occurs with patient 3 in any cohort, then up to 3 more patients
will enroll to the same cohort at a frequency of one patient every 28 days after the previous
patient has completed anti-OX40 assuming no DLT.

Inclusion Criteria:

1. Patients with measurable or evaluable metastatic adenocarcinoma of the prostate.
Either histologic or cytologic diagnosis is acceptable

2. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Appendix A.)

3. Age 18 years old or above

4. Laboratory values (performed within 28 days prior to enrollment) as follows:

- WBC ≥ 2000/microlitre

- Serum creatinine < 1.5 X upper limit of laboratory normal

- Hgb > 8g/dl (patients may be transfused to reach this level)

- Platelets > 100,000 cells/mm3

- Total bilirubin < 1.5 X upper limit of laboratory normal, unless due to Gilbert's
disease

- AST (SGOT) and ALT (SGPT) < 2.5 X upper limit of laboratory normal

- Alkaline phosphatase < 2.5 X upper limit of laboratory normal (If alkaline
phosphatase > 2.5 X upper limit of laboratory normal due to bone metastases, then
patient is eligible.)

- HIV 1 and 2 antibody Negative

- Hepatitis B surface antigen Negative

- Hepatitis C antibody Negative

- PSA > 2 ng/ml

- Testosterone < 50 ng/ml

5. Confirmed radiographic and/or PSA progression (using PCWG2 definitions) after at least
one androgen ablation regimen and docetaxel.Patients who refuse docetaxel chemotherapy
or who are not candidates for docetaxel are eligible to enroll.

6. At least one bone metastatic lesion amenable to radiation

7. Ability to give informed consent and comply with the protocol. Patients with a history
of psychiatric illness must be judged able to understand the investigational nature of
the study and the risks associated with the therapy

8. No active bleeding

9. No clinical coagulopathy (INR < 1.5, PT < 16 seconds, PTT < 38 seconds)

10. Anticipated lifespan greater than 12 weeks

11. Patients on LHRH agonists or bisphosphonates prior to study enrollment should continue
these medications without change

Exclusion Criteria:

1. Active infection.

2. Active autoimmune disease.

3. Previous treatment with mouse monoclonal antibodies

4. Need for chronic maintenance oral steroids.

5. Active brain metastatic disease. Patients with treated brain metastases with surgery,
gamma-knife radiosurgery or radiation and stable for at least 4 weeks and off steroids
are eligible.

6. Any medical or psychiatric condition that in the opinion of the PI would preclude
compliance with study procedures.