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

Study Description

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Brief Summary:

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, biologically effective dose, the pharmacokinetics, and the anti-cancer activity of CUDC-907.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma; Lymphoma	Drug: CUDC-907	Phase 1

Detailed Description:

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. The following dosing schedules may be examined, all consisting of 21-day cycles and including:

(i) continuous once daily (QD), (ii) twice weekly on Days 1, 4, 8, 11, 15, 18 (BIW) (iii) thrice weekly on Days 1, 3, 5, 8, 10, 12, 15, 17, 19 (TIW) (iv) four days on/three days off on Days 1-4, 8-11, and 15-18 (4/3), and (v) five days on/two days off on Days 1-5, 8-12, and 15-19 (5/2)

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, and may continue to receive additional treatment until disease progression has been documented or other treatment discontinuation criteria have been met.

MTD or BED expansion cohorts of up to 36 evaluable (e.g., up to 12 subjects in each of 2 or 3 specific tumor types or subtype) to better define the safety, tolerability and preliminary antitumor and pharmacodynamic activity of the study treatment, as well as suitability as an RP2D and schedule.

Safety and tolerability will be assessed by the incidence and severity of adverse events as determined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v4.03). A Safety Review Committee (SRC) comprised of the Medical Monitor, Principal Investigators, and Sponsor representatives, will be convened to review safety information and to decide upon dose escalation and further subject enrollment.

The antitumor activity of study treatment will be assessed according to 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 peripheral blood mononuclear cells (PBMC), plasma and tissue specimens (skin, tumor and bone marrow samples, where available).

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	88 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I Open Label, Multi-center, Dose-escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of Orally Administered CUDC-907, a PI3K and HDAC Inhibitor, in Subjects With Refractory or Relapsed Lymphoma or Multiple Myeloma
Study Start Date :	December 2012
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: CUDC-907 - Continuous Once Daily; 30-60 mg/day CUDC-907, orally administered continuous once daily in continuous 21 day cycles until disease progression or other discontinuation criteria are met.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - 2x/week; 60-240 mg/day CUDC-907, orally administered twice weekly on Days 1, 4, 8, 11, 15, 18 in continuous 21 day cycles until disease progression or other discontinuation criteria are met.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - 3x/week; 60-180 mg/day CUDC-907, orally administered thrice weekly on Days 1, 3, 5, 8, 10, 12, 15, 17, 19 in continuous 21 day cycles until disease progression or other discontinuation criteria are met.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - four days on/three days off; 60-180 mg/day CUDC-907, orally administered four days on/three days off on Days 1-4, 8-11, and 15-18 in continuous 21 day cycles until disease progression or other discontinuation criteria are met.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - five days on/two days off; 60-180 mg/day CUDC-907, orally administered five days on/two days off on Days 1-5, 8-12, and 15-19 in continuous 21 day cycles until disease progression or other discontinuation criteria are met.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - Expansion 5x/week; 60 mg of CUDC-907 on the 5 days on/2 days off dosing schedule.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - Expansion 3x/week; 120 mg of CUDC-907 on the 3 days on/4 days off dosing schedule.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - Combination Arm A; Combination Arm A will adminster CUDC-907 orally at the expansion 5/2 dose level (60 mg) plus rituximab given at 375 mg/m2 IV infusion. Rituximab will be administered on Day 1 of every cycle (21 days) for six cycles.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - Combination Arm B; Combination Arm B will give CUDC-907 orally at the expansion TIW dose level (120 mg) plus rituximab given at 375 mg/m2 IV infusion. Rituximab will be adminstered on Day 1 of every cycle (21 days) for six cycles.	Drug: CUDC-907; CUDC-907 administered orally with meals.
Experimental: CUDC-907 - Biocomparability Arm; A lead-in dose of CUDC-907 at 60 mg mesylate on Day -4 followed by besylate dosing beginning on C1D1 according to the 5/2 dosing schedule. The starting besylate dose will be 30 mg.	Drug: CUDC-907; CUDC-907 administered orally with meals.

Outcome Measures

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Primary Outcome Measures :

1. To determine the maximum tolerated dose (MTD) or biologically effective dose (BED) and recommended Phase 2 dose (RP2D) of oral CUDC-907 in patients with relapsed or refractory lymphoma or multiple myeloma [ Time Frame: 21 days (1 cycle of study treatment) ]
   Within any given study arm, the highest dose level studied at which fewer than 2 out of 6 subjects (< 33%) experience a dose limiting toxicity (DLT).

Secondary Outcome Measures :

1. To assess the safety and tolerability of CUDC-907 [ Time Frame: 18 months ]
   Number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).
2. 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 ]
   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).
3. To evaluate biomarkers of CUDC-907 activity [ Time Frame: Day 1, Day 8, and Day 15 of Cycle 1 dosing. ]
   Exploratory biological markers of CUDC-907 activity will be assessed in PBMCs, plasma, skin, hair follicle, tumor and bone marrow samples to explore downstream markers of PI3K and HDAC inhibition and cytokine levels.
4. To assess preliminary anti-cancer activity of CUDC-907 [ Time Frame: 24 months ]
   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).

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.
• 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 defined as more than 1 watery stools/day.
• 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 compliance with the protocol.
• No second primary malignancy within 2 years of study entry other than adequately treated non-melanoma skin or superficial bladder cancer, curatively treated carcinoma in situ of the cervix or other curatively treated solid tumor deemed by the investigator to be at low risk for recurrence.
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.

Contacts and Locations

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Locations

United States, California
USC/Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
United States, Florida
Florida Cancer Specialists
Sarasota, Florida, United States, 34232
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Oklahoma
Stephenson Cancer Center, University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

Curis, Inc.

The Leukemia and Lymphoma Society

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Oki Y, Kelly KR, Flinn I, Patel MR, Gharavi R, Ma A, Parker J, Hafeez A, Tuck D, Younes A. CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. Haematologica. 2017 Nov;102(11):1923-1930. doi: 10.3324/haematol.2017.172882. Epub 2017 Aug 31.

Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, Kelly KR, Copeland AR, Akins A, Clancy MS, Gong L, Wang J, Ma A, Viner JL, Oki Y. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016 May;17(5):622-31. doi: 10.1016/S1470-2045(15)00584-7. Epub 2016 Mar 31.

Responsible Party:	Curis, Inc.
ClinicalTrials.gov Identifier:	NCT01742988 History of Changes
Other Study ID Numbers:	CUDC-907-101
First Posted:	December 6, 2012
Last Update Posted:	February 5, 2018
Last Verified:	February 2018

Keywords provided by Curis, Inc.:

PI3K; HDAC; Open-Label; Dose-Escalation

Additional relevant MeSH terms:

Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders	Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders