Pentamidine + Salvage Chemo for Relapsed/Refractory Classical Hodgkin Lymphoma

The primary objective of this Phase I study is to determine the maximum tolerated dose (MTD)
of Pentamidine. A two-stage continual reassessment method (CRM) will be employed to determine
dose escalation levels and the maximum tolerated dose (MTD) of Pentamidine.

Specifically, a modified two-stage CRM will be employed with 2 patients per cohort at each
dose level. The trial starts with an escalation design from the lowest dose (2 mg/kg) with a
traditional 2+2 dose escalation method. After occurrence of the first DLT, dose assignment
will be determined by the CRM (2 patients/per cohort) using empirical model with restrictions
to avoid dose-skipping and escalation immediately after a toxicity outcome.

A maximum of 12 patients will be enrolled into the trial during the escalation phase. Once
the MTD is reached, an additional 4 patients will be treated at this dose. Thus, 6 or more
patients will be treated at the MTD.

The target DLT rate is 33% and the investigators choose to use 0.10, 0.20 and 0.33 as prior
toxicity distribution. CRM simulations indicate optimal performance of this design with high
dose recommendation probabilities (at least 48%) and more patients allocated to the correct
dose

Inclusion Criteria:

- Age 18 years old or older

- Eastern Cooperative Oncology Group (ECOG) performance status ≤2

- Subjects with histologically confirmed relapse or refractory cHL who had received a
front-line anthracycline-containing regimen.

- Subjects must have at least one measurable lesion >1.5cm as defined by the lymphoma
response criteria.

- Subjects must have recovered from their last prior chemotherapy; if they have received
an investigational agent, at least 5 half-lives must have expired to assure clearance
of prior therapy.

- Prior radiation should have been completed at least 4 weeks prior to study Day 1.

- Toxicities related to prior therapy must have returned to Grade 1 or less except for
alopecia. Peripheral neuropathy must be grade 2 or less.

- Adequate bone marrow function defined as: 1) Absolute neutrophil count ≥ 1000/µl and
2) Platelet count ≥ 50,000/µl

- Adequate organ function: 1) Creatinine Clearance (CrCl) >60 mL/min and 2) Aspartate
Aminotransferase (AST) ≤ 3 upper limit normal (ULN), and Alanine Aminotransferase
(ALT) ≤3 ULN, and Bilirubin ≤ 1.5 ULN (Unless they have Gillbert's disease)

- Ability to comply with the treatment, evaluations and required study follow-up.

Exclusion Criteria:

- Subjects with central nervous system involvement.

- Subjects with concomitant second malignancy (except adequately treated non-melanoma
skin cancer, ductal carcinoma in-situ, superficial bladder cancer, prostate cancer or
in situ cervical cancer) are excluded unless a complete remission was achieved at
least 3 years prior to study entry and no additional therapy is required or
anticipated.

- A serious uncontrolled medical disorder or active infection which impairs the ability
of the subject to receive protocol therapy or whose control is jeopardized by the
complication of this therapy.

- Prior organ allograft or allogeneic bone marrow transplantation.

- Positive for HIV (1/2) or known acquired immunodeficiency syndrome.

- Positive for hepatitis B Surface Ag, or antibody to hepatitis B core ag, or hepatitis
C antibody or hepatitis C RNA in serum.

- Ejection fraction less than 45% in subjects with prior anthracycline therapy
(measurement of ejection fraction is mandatory).

- Corrected QT interval (QTc) prolongation of more than 500.

- Women of reproductive age who are unwilling or unable to use an acceptable method to
minimize the risk of pregnancy for the entire study period and for at least 18 weeks
after the last dose of pentamidine.

- Women who are pregnant or breast-feeding.

- Women with a positive pregnancy test (serum assay) on enrollment or prior to
pentamidine administration.

- Sexually active men not using birth control if their partners are women of
reproductive age.

- Prisoner or subjects who are involuntarily incarcerated.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pentamidine and/or ifosfamide, carboplatin and etoposide.

- No investigational or commercial agents or therapies other than those specified by the
protocol may be administered with the intent to treat the patient's malignancy.