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Clinical Trials

Date: 2018-11-01

Type of information: update on patient enrollment

phase: 1b-2

Announcement: presentation of results at the 60th American Society of Hematology (ASH) Annual Meeting

Company: Trovagene (USA - CA)

Product: PCM-075 - onvansertib (1-(2-hydroxyethyl)-8-{[5-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy) phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide fumarate salt)

Action mechanism:

  • kinase inhibitor/Polo-like Kinase (PLK) inhibitor. PCM-075 is a highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK 1) enzyme, which is over-expressed in multiple hematologic and solid tumor cancers. Studies have shown that inhibition of polo-like-kinases can lead to tumor cell death, including a Phase 2 study in acute myeloid leukemia (AML) where response rates up to 31% were observed when used in conjunction with a standard therapy for AML (low-dose cytarabine-LDAC) versus treatment with LDAC alone with a 13.3% response rate.
  • PCM-075 only targets PLK1 isoform (not PLK2 or PLK3), is oral, has a 24-hour drug half-life with reversible on-target hematologic toxicities. Trovagene believes that targeting only PLK1 with reversible on-target activity and an improved dose/scheduling protocol can significantly improve on the long-term outcome observed in previous studies with a PLK inhibitor in AML.
  • PCM-075 has demonstrated synergy in preclinical studies with over 10 chemotherapeutic and target agents used in hematologic and solid tumor cancers, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins. Trovagene believes the combination of its targeted PLK-1 inhibitor, PCM-075, with other compounds has the potential for improved clinical efficacy in acute myeloid leukemia, castration-resistant prostate cancer, non-Hodgkin lymphoma, triple negative breast cancer and adrenocortical carcinoma.

Disease: acute myeloid leukemia (AML)

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

  • The purpose of the phase 1b/2 study is to determine whether PCM-075 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 PCM-075 in combination with decitabine or and PCM-075 in combination with low-dose cytarabine. In the phase 2 portion of the study, one regimen (either PCM-075 in combination with decitabine or PCM-075 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.
  • The Phase 1b/2 clinical trial in AML is being led by Hematologist Jorge Eduardo Cortes, M.D., Deputy Department Chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. (NCT03303339)

Latest news:

  • • On November 1, 2018, Trovagene announced that its abstract highlighting data from onvansertib in acute myeloid leukemia has been accepted for presentation at the 60th American Society of Hematology (ASH) Annual Meeting, December 1-4, 2018. The presentation will include data from the ongoing Phase 1b/2 clinical trial of onvansertib (PCM-075), a first-in-class, 3rd generation, highly-selective oral Polo-like Kinase 1 (PLK1) Inhibitor, in combination with standard-of-care low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory AML. The combination regimen has demonstrated that it is safe and well-tolerated in patients treated to-date, and further dose-escalation is continuing. The integration of a predicative biomarker strategy in the trial to help identify patients who are most likely to respond to treatment has yielded evidence of PLK1 inhibition in a number of treated patients and this appears to be correlated with decreases in circulating leukemic blast cells and/or bone marrow blast cells, indicating a potential clinical response.
  • • On September 27, 2018, Trovagene announced completion of the second dosing cohort of onvansertib in combination with standard-of-care decitabine, in its Phase 1b/2 clinical trial in patients with acute myeloid leukemia. All three patients in the cohort successfully completed treatment with onvansertib at 18mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with decitabine and the combination was well tolerated. The Safety Review Committee (SRC) has recommended escalating to the next dose level of Onvansertib at 27mg/m2 (approximately a 50% increase) in combination with decitabine.
  • • On September 5, 2018, Trovagene announced it has developed a method for predicting response to treatment by measuring the ability of onvansertib to inhibit PLK1 in patients with acute myeloid leukemia. PLK1 uniquely phosphorylates translational control tumor protein (TCTP) to form pTCTP and inhibition of this enzymatic activity by Onvansertib appears to be predictive of patient response to treatment. In the ongoing Phase 1b/2 open label clinical trial in AML, PLK1 inhibition is being assessed 3-hours following administration, at the approximate peak concentration (Cmax) of onvansertib. In the first six patients treated, the greatest target engagement, or inhibition of PLK1, was observed in the three patients who showed a response to treatment.
  • Trovagene has filed a U.S. patent application with the United States Patent and Trademark Office (USPTO) to protect its method for evaluating responsiveness of a cancer to a Polo-like Kinase 1 (PLK1) inhibitor by determining the ability of the PLK1 inhibitor to inhibit phosphorylation of a unique target of PLK1 in cells of the cancer.
  • • On June 27, 2018, Trovagene announced preliminary clinical data from the first dosing cohort showing a treatment effect with PCM-075 in combination with low-dose cytarabine (LDAC) or decitabine, as measured by decreases in leukemic cells in both peripheral blood and bone marrow in patients in its ongoing Phase 1b/2 trial in relapsed or refractory acute myeloid leukemia.
  • Both blood and bone marrow samples were obtained from patients with relapsed or refractory AML enrolled in the Phase 1b/2 trial prior to, and at timepoints following administration of PCM-075, in combination with cytarabine or decitabine. In the first dose level, seven patients were treated with PCM-075 at 12 mg/m2 in combination with either LDAC or decitabine. One patient was not evaluable for safety due to rapid disease progression. Among the other 6 patients, no dose-limiting toxicities (DLTs) were observed that would prohibit further escalation of the PCM-075 dosing. Three patients exhibited substantial reductions in the percentage of both circulating leukemic cells within the blood and leukemic cells within the bone marrow. Two of these three patients continued on treatment in the second cycle and further decreases in circulating leukemic cells in the blood and within the bone marrow were observed. One patient had a decrease in his bone marrow blasts from 96% to 40% at the end of cycle 2 and has continued on treatment in cycle 3. The next dose level cohort of PCM-075 at 18 mg/m2 in combination with LDAC or decitabine is currently enrolling and dosing patients.
  • In addition, Translational Control Tumor Protein (TCTP), which is uniquely phosphorylated by PLK1, was used to evaluate PLK1 inhibition by PCM-075. Data presented by Trovagene at the 2018 American Association for Cancer Research (AACR) showed that PCM-075 decreases phosphorylated TCTP (pTCTP) in AML cell lines. In these same cell lines pTCTP levels were unaffected by treatment with either LDAC or decitabine.
  • PLK1 inhibition in the Phase 1b/2 AML trial is being assessed in patients 3-hours following administration of PCM-075 in combination with LDAC or decitabine, when PCM-075 levels are expected to be at their peak concentration (Cmax). Significant reductions in PLK1, as measured by pTCTP levels, were observed in the circulating blood cells in four of six patients treated with PCM-075 in combination with cytarabine or decitabine. Three of these four patients also had significant reductions in circulating blast cells during the treatment cycle.
  • • On June 15, 2018, Trovagene announced completion of the first dose cohort of PCM-075, a highly-selective Polo-like Kinase 1 (PLK1) Inhibitor, in combination with decitabine, in its Phase 1b/2 clinical trial in patients with acute myeloid leukemia (AML). Three patients were treated with PCM-075 at 12 mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with decitabine. The combination of PCM-075 and decitabine was well tolerated in all patients. The independent Safety Review Committee (SRC) has recommended escalating to the second dose cohort of three patients at 18 mg/mof PCM-075 (approximately a 50% increase) in combination with decitabine
  • This is the second dose cohort to be completed in the Phase 1b/2 open-label AML study of PCM-075 in combination with standard-of-care chemotherapy.
  • The PCM-075 dose level may be increased by 50% increments on either LDAC or decitabine in successive cohorts of three patients until a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) is achieved. The MTD or RP2D will be used in the Phase 2 segment of the trial to evaluate antitumor activity and to continue to assess the safety and tolerability of PCM-075 in combination with standard-of-care chemotherapy.
  • • On May 17, 2018, Trovagene announced the completion of the first dose cohort in its Phase 1b/2 clinical trial of PCM-075 in combination with LDAC, in Acute Myeloid Leukemia (AML). Three patients were treated with PCM-075 at 12 mg/m2, administered orally, once daily, on days 1-5 of the treatment cycle, in combination with LDAC.  Patients eligible for Phase 1b have relapsed or refractory disease and may have received as many as three prior regimens for treatment of their AML. The combination of PCM-075 and LDAC was well tolerated in all patients.  The independent Safety Review Committee (SRC) has recommended escalating to the second dose cohort of three patients at PCM-075 at 18 mg/m(approximately a 50% increase) in combination with LDAC.
  •  On April 17, 2018, Trovagene announced the presentation of pharmacodynamic and biomarker data from the first patient to complete a safety treatment cycle in its Phase 1b/2 clinical trial of PCM-075 in AML. The poster entitled Pharmacodynamic and Tumor Biomarker Analysis of a PLK1 Inhibitor, PCM-075, in a Phase 1b/2 Trial for Acute Myeloid Leukemia presents the methodology developed to track dynamic changes in blood leukemic cells, genomic alterations and PLK1 inhibition in AML patients treated with PCM-075 in combination with LDAC.
  • PCM-075 appeared to be well tolerated with the first of three patients enrolled in the initial Phase 1b dose-escalation cohort consenting to, and completing, a second cycle of treatment with PCM-075 plus LDAC.  The two additional patients in this cohort are on treatment and receiving a 12 mg/m2 oral, daily dose of PCM-075 (Days 1-5 in a 28-day cycle) in combination with LDAC.  Additionally, patient enrollment is also complete in the first Phase 1b dose-escalation cohort of three patients to receive a 12 mg/m2 oral, daily dose of PCM-075 (Days 1-5 in a 28-day cycle) in combination with decitabine, with two patients currently receiving cycle-one treatment.  The PCM-075 dose will be escalated in the 1bsegment of the trial until a Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) is achieved.• On February 13, 2018, Trovagene announced that the initial patient successfully completed the first cycle 1 of treatment in its Phase 1b/2 multicenter trial of PCM-075 in combination with low-dose cytarabine (LDAC) in patients with AML. The patient tolerated the combination well and correlative analyses of blood samples, taken at specified time points, also indicated activity on leukemic blood cells. A significant decrease in the percentage of blood leukemic cells was observed within 24 hours of administering PCM-075 + LDAC. By day 15, within the treatment cycle, the greatest effect was observed with blood leukemic cells showing a decrease from greater than 40% to less than 5%. Additionally, the same tumor DNA mutations (ASXL1 and SRSF2) were detected in the bone marrow and blood, indicating consistency across samples and validity of the analyses. Both DNA mutations appeared to quantitatively track with the decrease in blood leukemic cells.
  • Trovagene also announced the addition of two leading institutions, Yale Cancer Center and principal investigator Amer M. Zeidan, MBBS, MHS, and Kansas University Cancer Center and principal investigator Tara Lin, MD, to conduct its Phase 1b/2 open-label, multicenter trial of PCM-075 in patients with AML. The trial, which is being led by hematologist Jorge Cortes, M.D., Deputy Department Chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, will be conducted at 10 sites throughout the U.S. and is expected to enroll approximately 74 patients.
  • • On February 6, 2018, Trovagene announced that the first patient has completed the first cycle of dosing with PCM-075 in combination with low-dose cytarabine in its Phase 1b/2 multicenter trial of patients with acute myeloid leukemia. Two clinical trial sites are currently screening and enrolling patients and five additional sites are planned to be activated by the end of the first quarter. of-care chemotherapy for these patients."
  • • On December 21, 2017, Trovagene announced the activation of the second clinical trial site for its Phase 1b/2 multicenter trial of PCM-075 in patients with AML, with Virginia Piper Cancer Institute and Principal Investigator, Dr. Michaela Tsai. The primary objectives of this Phase 1b/2 trial in AML are to evaluate the safety of PCM-075 in combination with either low-dose cytarabine or decitabine in subjects and to identify the maximum tolerated dose (MTD) in Phase 1b to administer to further evaluate the safety and preliminary efficacy in Phase 2.
  • • On November 13, 2017, Trovagene announced the activation of its clinical trial site for its Phase 1b/2 multicenter trial of PCM-075 in patients with acute myeloid leukemia, with Virginia Cancer Specialists and Principal Investigator, Dr. Alexander Spira. This trial will enroll subjects in the Phase 1b who have relapsed or have resistant disease to no more than three prior regimens.
 

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