PCM-075 for Hematologic and Solid Tumor Cancers

The only oral, highly-selective Polo-like Kinase 1 (PLK1) inhibitor currently in clinical trials

The Need for New
Cancer Therapies

PCM-075 was developed to have high selectivity to PLK1 (at low nanomolar IC50 levels), to be administered orally, and to have a relatively short drug half-life of approximately 24 hours compared to other pan PLK inhibitors. A safety study of PCM-075 has been successfully completed in patients with advanced metastatic solid tumors and published in 2017 in Investigational New Drugs.

We currently are enrolling a Phase 1b/2 open-label clinical trial of PCM-075 in combination with standard-of-care chemotherapy in patients with Acute Myeloid Leukemia (AML). In addition, we plan to initiate a Phase 2 open-label clinical trial of PCM-075 in combination with Zytiga® (abiraterone acetate)/Prednisone in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC).

Why PCM-075?

Characteristic Benefit PCM-075
Oral; 24-Hour Half-Life
  • Enables sustaining drug levels without compromising safety
Selective for PLK1
  • Provides highly-targeted therapy for G2/M cell-cycle division checkpoint
  • Reversible, on-target side effects, consistent with the expected mechanism of action[1]Investigator Brochure for PCM-075, 22 June 2017 Trovagene data on file
Synergistic in Combination[2]Preclinical data on file with PCM-075 in combination with chemo and targeted therapeutics;
  • Combination therapies potentially yielding “1+1=3” clinical activity
  • Demonstrated synergy with (e.g., cytarabine, paclitaxel and abiraterone)
  • Enhances mechanism of action without increasing on-target toxicities
Tumor Cell Sensitivity
  • Normal cells are 10-fold less sensitive than tumor cells to induced cell death[3]Valsasina et al., Molecular Cancer Therapeutics; 11(4) April 2012;
  • No GI disorders, mucositis, or alopecia observed in Phase 1 solid tumor study
Resistance Mechanism
  • Ability to induce cell death in tumor cells that express transporters (e.g. MDR1)[4]Investigator Brochure for PCM-075, 22 June 2017 Trovagene data on file

PCM-075 is Synergistic in Combination with Chemotherapeutics and Targeted Therapies

High PLK1 expression is associated with the most aggressive forms of hematologic and solid tumor cancers. PCM‑075 presents an exciting opportunity to be used in combination with chermotherapeutics and targeted therapies and could potentially enhance the efficacy of current and future standard-of-care therapies.

In preclinical studies, synergy (interaction of discrete drugs such that the total effect is greater than the sum of the individual effects) has been demonstrated with PCM-075 when used in combination with more than ten different chemotherapeutics, including cisplatin, cytarabine, doxorubicin, gemcitabine and paclitaxel, as well as targeted therapies, such as abiraterone acetate (Zytiga®), HDAC inhibitors, such as belinostat (Beleodaq®), Quizartinib (AC220), a development stage FLT3 inhibitor, and bortezomib (Velcade®). These therapeutics are used clinically for the treatment of many hematologic and solid tumor cancers, including Acute Myeloid Leukemia (AML), Non-Hodgkin Lymphoma (NHL), metastatic Castration-Resistant Prostate Cancer (mCRPC), and Triple Negative Breast Cancer (TNBC).

Potentially
Synergistic Drugs [5]Alphabetical order [6]Predinical data on file with PCM-075 and these combined therapeutics
Abiraterone acetate
Bevacizumab
Bortezomib
Cisplatin
Cytarabine
Doxorubicin
FLT3 Inhibitors (Quizartinib)
Gemcitabine
HDAC Inhibitors (Belinostat)
Paclitaxel
Associated Cancers[7]Predinical data on file with PCM-075 and these combined therapeutics
Leukemias/Lymphomas:
  • Acute Myeloid Leukemia
  • Acute Lymphocytic Leukemia
  • Non-Hodgkin Leukemia
  • Multiple Myeloma
Solid Tumors Cancers:
  • Castration-Resistant Prostate
  • Adrenocortical Carcinoma
  • Triple Negative Breast
  • Sarcomas
  • Small Cell Lung
  • Colon

Treating Acute Myeloid Leukemia with PCM-075

AML is an aggressive cancer of the blood and bone marrow with approximately 20,000 new cases in the U.S each year.

We see the FDA’s granting of orphan drug designation for PCM-075 as underscoring the medical need for new therapies for patients with AML and an important step forward in our clinical development program.

Phase 1b/2 Open-Label Clinical Trial of PCM-075 in Combination with Low-Dose Cytarabine or Decitabine in Acute Myeloid Leukemia (AML)

We are currently enrolling patients in our AML trial at eight sites across the U.S.

Acute Myeloid Leukemia

leukemia
  • Aggressive hematologic malignancy of immature blood cells
  • Incidence: 20,000* new cases and 10,400 deaths annually in the U.S.
  • Prognosis: 5 year survival rate is 25%
  • Treatment options vary based on patient condition / age
  • Genetically diverse landscape

Clinical Trial Objectives:

  • Assess the safety of PCM‑075 in combination with standard-of-care chemotherapy
  • Determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) for use in the Phase 2 segment
  • Evaluate preliminary anti-tumor activity of PCM‑075 in combination with standard-of-care chemotherapy
  • Explore pharmacodynamic and correlative biomarker analyses to identify patients most likely to respond to therapy

Evaluation of Efficacy of PCM-075 for MV-4-11 Human Acute Myeloid Leukemia (AML) Xenograft Model in NODSCID Mice

Synergy Demonstrated with PCM‑075 + FLT3 Inhibitor (Quizartinib) in AML

  • 30% of AML patients harbor an FLT3 mutation[8]Kindler et al, Blood 2010, 116:5089-10.
  • Midostaurin (FDA approved) and three additional FLT3 inhibitors, including quizartinib, are currently in Phase 3 clinical development[9]Stone et al, N Engl J Med 2017, 377:454-64.
  • The combination of PCM-075 and quizartinib demonstrated 97% tumor growth inhibition and regression in FLT3 AML xenograft model[10]Data on file at Trovagene, Inc.

Treating Metastatic Castration-Resistant Prostate Cancer with PCM-075

25,000 men progress to metastatic prostate cancer resistant to standard androgen-deprivation therapy, annually.

There is an ongoing need to increase the duration of response to current therapies used to treat patients with metastatic Castration-Resistant Prostate Cancer (mCRPC)

Phase 2 Open-Label Clinical Trial of PCM-075 in Combination with Zytiga® (abiraterone acetate)/Prednisone in mCRPC

We currently have plans for a Phase 2 clinical trial in mCRPC at three clinical sites

Metastatic Castration-Resistant Prostate Cancer

Prostate Cancer
  • 25,000 men progress to metastatic prostate cancer resistant to standard androgen-deprivation therapy, anually
  • Ongoing need to increase duration of response for mCRPC patients

Clinical Trial Objectives:

  • Evaluate the effect of PCM‑075 in combination with Zytiga® (aberaterone acetate)/Prednisone on disease control as assessed by prostate-specific antigen (PSA) decline or stabilization
  • Observe the effects of PCM‑075 in combination with abiraterone and Prednisone on change in PSA relative to baseline in patients with mCRPC showing early signs of disease progression
  • Assess the safety of PCM‑075 in combination with Zytiga® (aberaterone acetate)/Prednisone in patients with mCRPC

Synergy Demonstrated with PCM‑075 + Zytiga® (abiraterone acetate)/Prednisone in mCRPC

Current therapies used to treat mCRPC include abiraterone, enzalutamide and docetaxel. However, patients develop resistance to abiraterone and enzalutamide generally within 9-15 months and do not respond well to subsequent therapies.

PCM‑075 in combination with abiraterone may prolong the response to anti-androgen therapy allowing for more effective mCRPC combination therapies.

  • PCM‑075 in combination with abiraterone is shown to induce cell death in prostate cancer cell lines
  • Combination appears to enhance the PCM-075 mechanism of action of arresting cells during mitosis[11]Yaffe, Michael, MD and Trovagene, 2017
  • There continues to be a large medical need to extend the benefit of response to abiraterone in mCRPC

C4-2 Castration-Resistant Prostate Cancer Cells Increased Sensitivity to Abiraterone in the Presence of PCM-075

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