Onvansertib in Combination With Either Low-dose Cytarabine or Decitabine in Adult Patients With Acute Myeloid Leukemia (AML).

• Sponsor: Trovagene, Inc.
• Information provided by (Responsible Party): Trovagene, Inc.

Study Description

Brief Summary:

The purpose of the phase 1b/2 study is to determine whether Onvansertib given orally daily for 5 consecutive days every 28 days is safe and tolerable in adult patients who have relapsed/refractory Acute Myeloid Leukemia, or are ineligible for intensive induction therapy, and to determine the maximum tolerated dose or recommended phase 2 dose of Onvansertib in combination with decitabine or and Onvansertib in combination with low-dose cytarabine. In the phase 2 portion of the study, one regimen (either Onvansertib in combination with decitabine or Onvansertib in combination with low-dose cytarabine) will be studied to provide further data on the safety profile of the combination and to preliminarily assess the activity of the chosen combination in patients with untreated AML who are not candidates for aggressive induction therapy, or who have received one prior treatment for their AML.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia	Drug: Onvansertib; Drug: Cytarabine; Drug: Decitabine	Phase 1; Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	116 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1b/2 Study of PCM-075 (Onvansertib) in Combination With Either Low-Dose Cytarabine or Decitabine in Subjects With Acute Myeloid Leukemia (AML)
Actual Study Start Date :	November 17, 2017
Estimated Primary Completion Date :	January 31, 2020
Estimated Study Completion Date :	May 31, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1b: Onvansertib + low-dose cytarabine; Onvansertib, administered in escalating doses orally Day 1 through Day 5 every 28 days (1 cycle) in combination with cytarabine, which will be administered in all cohorts as 20 mg/m2 subcutaneously, once daily on Day 1 through Day 10 every 28 days (1 cycle). Onvansertib administration, in combination with cytarabine, will be initiated at a starting dose of 12 mg/m2 orally, daily for 5 days. Onvansertib dose will be escalated in successive cohorts until Maximum Tolerated Dose/Recommended Phase 2 Dose is achieved.	Drug: Onvansertib; Onvansertib orally; Drug: Cytarabine; subcutaneously
Experimental: Phase 1b: Onvansertib + decitabine; Onvansertib will be administered in escalating doses orally, Day 1 through Day 5 every 28 days (1 cycle) in combination with decitabine, administered consistently in all cohorts as 20 mg/m2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle). Onvansertib administration, in combination with decitabine, will be initiated at a starting dose of 12 mg/m2 orally, daily for 5 days (Day 1 through Day 5). Onvansertib dose will be escalated in successive cohorts until Maximum Tolerated Dose/Recommended Phase 2 Dose is achieved.	Drug: Onvansertib; Onvansertib orally; Drug: Decitabine; intravenously
Experimental: Phase 2: Onvansertib + cytarabine or decitabine; Onvansertib Recommended Phase 2 Dose, orally Day 1 through Day 5 every 28 days (1 cycle) and either cytarabine, 20 mg/m2 subcutaneously, once daily on Day 1 through Day 10 every 28 days (1 cycle), or decitabine, administered consistently as 20 mg/m2 intravenously over 1 hour on Day 1 through Day 5 every 28 days (1 cycle), with treatment modifications or delays based on return of hematopoietic function to baseline or Grade ≤1 toxicity for optimal subject management.	Drug: Onvansertib; Onvansertib orally; Drug: Cytarabine; subcutaneously; Drug: Decitabine; intravenously

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
   DLT is defined as an adverse reaction or suspected adverse reaction, during the 28 days according to the Common Terminology Criteria for Adverse Events (CTCAE).
2. Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
   The severity of each AE will be graded using the Common Terminology Criteria for Adverse Events (CTCAE).
3. Number of Participants With Clinically Significant Change from Baseline in Electrocardiograms (ECG) [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
4. Number of Participants with Clinically Significant Physical Examination Findings [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
5. Number of Participants With Clinically Significant Change From Baseline in Body Weight [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
6. Number of Participants With Clinically Significant Change From Baseline in vital signs [ Time Frame: Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
7. Number of Participants With Clinically Significant Change From Baseline in laboratory parameters [ Time Frame: Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months)] ]
8. Number of Participants With Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status [ Time Frame: Baseline and end of trial (approximately up to up to 27 months) ]
   ECOG performance measured on-therapy.
9. Phase 2: Rate of Complete Response (CR) + Complete Response with Incomplete Blood Count Recovery (CRi) [ Time Frame: Baseline and end of trial (up to up to 27 months) ]
   Defined as a morphologic leukemia-free state.

Secondary Outcome Measures :

1. Phase 2: Rate of achievement of a morphologic Leukemia-free (MLF) State [ Time Frame: Baseline and end of trial (up to 27 months) ]
   Defined as bone marrow (BM) <5% blasts in an aspirate with spicules (a BM biopsy should be performed if spicules are absent) and no blasts with Auer rods or persistence of extramedullary disease.
2. Phase 2: Rate of partial response (PR) [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
   All of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate and a normalization of blood counts
3. Phase 2: Duration of response (DOR) [ Time Frame: Baseline and end of trial (up to 27 months) ]
   Time from documentation of response until documentation of recurrence of or progression of disease.
4. Phase 2: Event-free survival (EFS) [ Time Frame: Baseline and end of trial (up to 27 months) ]
   Time from enrollment until disease progression or death from any cause.
5. Phase 2: Overall survival (OS) [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 27 months) ]
   Time from enrollment until death from any cause
6. Pharmacokinetic parameter: Maximum Observed Plasma Concentration (Cmax) for Onvansertib [ Time Frame: Up to 24 months ]
7. Pharmacokinetic parameter: Minimum Observed Plasma Trough Concentration (Cmin) for Onvansertib [ Time Frame: Up to 24 months ]
8. Pharmacokinetic parameter: Time to Reach the Maximum Observed Plasma Concentration (Tmax) for Onvansertib [ Time Frame: Up to 24 months ]
9. Pharmacokinetic parameter: Area under the curve over the first 24 hours AUC(0-24) for Onvansertib [ Time Frame: Up to 24 months ]
10. Pharmacokinetic parameter: Plasma terminal elimination half-life (t1/2) for Onvansertib [ Time Frame: Up to 24 months ]

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:

1. Disease Status and Prior Therapy:

   1. Histologically confirmed AML with >20% blasts
   2. Phase 1b: Participants with AML who are refractory to or have relapsed after initial treatment for their disease, with no more than three prior lines of therapy. Participants who have received prior treatment with cytarabine or decitabine are not excluded.
   3. Phase 2:

   i. Participants with AML who are refractory to, or have relapsed after, initial treatment for their disease, with no more than one prior line of therapy, and are judged not to be candidates for re-induction therapy that includes hematopoietic cell transplantation. Participants who have received prior cytarabine or decitabine are not excluded.

   OR

   ii. Participants with newly diagnosed, untreated AML ineligible for, or who have refused, standard intensive induction therapy

2. Age ≥18 years
3. ECOG performance status ≤2
4. Participants must be willing and able to review, understand, and provide written consent before starting any study-specific procedures or therapy.

5. All men and women must agree to practice effective contraception during the entire study period and after discontinuing study drug, unless documentation of infertility exists

   1. Sexually active, fertile women must use two effective forms of contraception (abstinence, intrauterine device, oral contraceptive, or double barrier device) from the time of informed consent and until at least 6 months after discontinuing study drug
   2. Sexually active men and their sexual partners must use effective contraceptive methods from the time of participant informed consent and until at least 3 months after discontinuing study drug

Exclusion Criteria:

1. Treatment-related AML or acute promyelocytic leukemia (APL)
2. Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death
3. Clinical evidence of active central nervous system leukemia at the time of screening
4. Alanine aminotransferase and/or aspartate aminotransferase ≥2.5 x upper limit of normal (ULN)
5. Total bilirubin > 2.0 mg/dL (or > 3.0 mg/dL in participants with documented Gilbert syndrome)
6. Serum creatinine ≥2.0 mg/dL
7. New York Heart Association Class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition, or hypertensive or metabolic condition
8. Myocardial infarction in the previous 12 weeks (from the start of treatment)
9. Resting left ventricular ejection fraction <50% at the time of screening
10. QT (Interval from the beginning of the QRS complex to the end of the T wave on an electrocardiogram) interval with Fridericia's correction [QTcF] >450 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during screening and that result may be used to determine eligibility.
11. Planned concomitant use of medications known to prolong the QT/QTc interval
12. Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia
13. Active and uncontrolled disease (other than AML) or infection as judged by the treating physician
14. Treatment with systemic therapy for the primary disease within 14 days (except for hydroxyurea or isolated doses of cytarabine or decitabine for white blood cell control)
15. Grade 2 or greater toxicities from prior therapy, except for Grade 2 toxicities that are not expected to resolve and that in the judgment of the Investigator do not pose a significant safety risk to subject participation.
16. Participants with any other medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the participant's ability to sign the informed consent form or his/her ability to cooperate and participate in the study, or to interfere with the interpretation of the results

Contacts and Locations

Contacts

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Contact: Central Contact Lead	858-952-7652	VKelemen@trovagene.com

Locations

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United States, California
University of California Los Angeles	Recruiting
Los Angeles, California, United States, 90095
Contact 310-206-5511
United States, Connecticut
Yale University	Recruiting
New Haven, Connecticut, United States, 06510
Contact 203-200-4363
United States, Kansas
University of Kansas Cancer Center	Recruiting
Westwood, Kansas, United States, 66205
Contact 585-957-4381
United States, Minnesota
Allina Health Virginia Piper Cancer Institute	Recruiting
Minneapolis, Minnesota, United States, 55407
Contact 612-884-6300
United States, New York
Roswell Park Cancer Institute	Recruiting
Buffalo, New York, United States, 14263
Contact 716-845-3544
United States, Texas
University of Texas Southwestern Medical Center	Recruiting
Dallas, Texas, United States, 75390
Contact 214-648-1906
MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Contact 713-794-5783
United States, Virginia
Virginia Cancer Specialists - Fairfax Office	Recruiting
Fairfax, Virginia, United States, 22031
Contact 703-208-3173
United States, Washington
Seattle Cancer Care Alliance	Recruiting
Seattle, Washington, United States, 98109
Contact 855-557-0555

Sponsors and Collaborators

Trovagene, Inc.

More Information

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Responsible Party:	Trovagene, Inc.
ClinicalTrials.gov Identifier:	NCT03303339 History of Changes
Other Study ID Numbers:	TROV-052; U1111-1201-6416 ( Other Identifier: WHO )
First Posted:	October 6, 2017
Last Update Posted:	March 1, 2019
Last Verified:	February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Trovagene, Inc.:

PLK1; PLK Inhibitor; Onvansertib

Additional relevant MeSH terms:

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Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Cytarabine; Decitabine; Antimetabolites, Antineoplastic; Antimetabolites	Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Enzyme Inhibitors