Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of CUDC-907 in Patients With Lymphoma or Multiple Myeloma

• To assess the safety and tolerability of CUDC-907 [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  Number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).
• To assess pharmacokinetics (PK) of oral CUDC-907 [ Time Frame: Pre-dose to 24 hours post-dose on the first and fifteenth day of study drug dosing ] [ Designated as safety issue: No ]
  Pharmacokinetic parameters will include area under the concentration-time curve (AUC), maximum plasma concentration (Cmax), half-life (T1/2), clearance (Cl) and volume of distribution (Vd).
• To evaluate biomarkers of CUDC-907 activity [ Time Frame: Day 1, Day 8, and Day 15 of Cycle 1 dosing. ] [ Designated as safety issue: No ]

  Pre- and post-dose changes in acetylated histone H3 protein levels in peripheral blood mononuclear cells (PBMCs) on Day 1 and Day 15 of Cycle 1 dosing.

  Pre-dose values in acetylated histone H3 protein levels in PBMCs on Day 8 of Cycle 1 dosing.

• To assess preliminary anti-cancer activity of CUDC-907 [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  The Investigator will evaluate each subject for response to therapy according to standard response criteria for each individual subject's tumor type (e.g., Revised Response Criteria for Malignant Lymphoma and the International Uniform Response Criteria for Multiple Myeloma).

This is a phase I, open-label, dose-escalation study of CUDC-907 in patients with refractory or relapsed lymphoma or multiple myeloma. CUDC-907 is a multi-targeted agent designed to inhibit phosphoinositide 3-kinase(PI3K)and histone deacetylase (HDAC). The study is designed to assess the safety, including the maximum tolerated dose, the pharmacokinetics, and the anti-cancer activity of CUDC-907.

This is a Phase I, open-label, multi-center dose-escalation trial evaluating the safety and tolerability of CUDC-907 as a single agent administered orally, once daily, to patients with relapsed or refractory lymphoma or multiple myeloma.

Sequential dose escalation cohorts of oral CUDC-907 are planned. Subject enrollment and dose escalation will proceed according to a standard 3+3 design. In the absence of DLT, each subject will be treated for a minimum of 21 days of continuous daily dosing, and may continue to receive additional treatment until disease progression has been documented or other treatment discontinuation criteria have been met. No intrasubject dose escalation will be allowed. An MTD expansion cohort of up to 12 evaluable subjects may also be enrolled in order to better define the safety, tolerability and activity of the study treatment.

Safety and tolerability will be assessed by the incidence and severity of adverse events as determined by NCI Common Terminology Criteria for Adverse Events (CTCAE v4.03).

The antitumor activity of study treatment will be assessed according standard response criteria as appropriate for each individual subject's tumor type (e.g., Revised Response Criteria for Malignant Lymphoma and the International Uniform Response Criteria for Multiple Myeloma).

Exploratory biological markers of activity will be assessed in PBMC and plasma.

• Multiple Myeloma
• Lymphoma

Inclusion Criteria:

• Subjects of ≥ 18 years of age with histopathologically confirmed diagnosis of lymphoma or multiple myeloma that is refractory to or relapsed after at least 2 prior regimens.
• Measurable or evaluable disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Recovery to Grade 1 or baseline of any toxicity due to prior systemic treatments (excluding alopecia).
• Absolute neutrophil count ≥ 1,000/µL; platelets ≥ 75,000/µL; creatinine ≤ 1.5x upper limit of normal (ULN); total bilirubin ≤ 1.5x ULN; AST/ALT ≤ 2.5x ULN. For subjects with documented liver metastases, the AST/ALT may be ≤ 5x ULN.
• Life expectancy of at least 3 months.
• Women of child bearing potential must have a negative serum pregnancy test.
• Men and women of child bearing potential must agree to use adequate birth control throughout their participation in the study and for 30 days following the last study treatment.
• Able to provide written informed consent and to follow protocol requirements.

Exclusion Criteria:

• Systemic anticancer therapy within 3 weeks of study entry, except for nitrosoureas or mitomycin C (6 weeks).
• Graft vs. host disease following prior allogeneic transplant within 3 months prior to study treatment.
• Other investigational agents within 21 days prior to study treatment.
• Prior treatment with a PI3K inhibitor.
• Peripheral neuropathy of Grade 2 or higher within 14 days prior to study treatment.
• Pregnant or lactating/breast-feeding women.
• Ongoing treatment with chronic immunosuppressants.
• Active CNS lymphoma.
• Known gastrointestinal condition that would interfere with swallowing or the oral absorption or tolerance of CUDC-907.
• Ongoing diarrhea of any grade (per NCI CTCAE v4.03).
• Serious infection requiring systemic antibiotic therapy within 14 days prior to study treatment.
• Uncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.
• Unstable or clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize the safety of a subject and/or their compliance with the protocol.
• Prior malignancy within 2 years except non-melanoma skin cancer
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.