On February 11, 2020 Phosplatin Therapeutics LLC, a clinical stage pharmaceutical company focused on oncology drug development, reported it will present clinical data in metastatic castration resistant prostate cancer (mCRPC) at the Genitourinary Cancers Symposium, demonstrating safety and biological activity of PT-112 in a heavily refractory population of late-stage prostate cancer patients from two separate Phase I studies (Press release, Phosplatin, FEB 11, 2020, View Source [SID1234554185]).
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"The unmet need in heavily pre-treated patients with mCRPC is extensive, and we believe that PT-112’s immunogenic cell death (ICD) induction and its biodistribution, including osteotropism, are responsible for the encouraging drug activity we have observed among Phase I patients," said Jose Jimeno, MD, PhD, Chief Medical Officer. "These are the first data presented publicly with PT-112 used in a single-disease sub-population. PT-112’s demonstrable activity and attractive safety profile in both the monotherapy and combination cohorts underscores the potential for future clinical development in this late-stage setting of mCRPC," said Robert Fallon, President & CEO of Phosplatin Therapeutics.
Phosplatin’s novel Immunogenic Cell Death (ICD) inducing agent, PT-112, is shown to be well-tolerated with evidence of drug activity in advanced mCRPC as both monotherapy and in combination with avelumab*, an anti-PD-L1 immune checkpoint inhibitor, in heavily pre-treated patients with prostate cancer with a median of 6 prior lines of therapy. Bone pain improvement and nearly universal observation of alkaline phosphatase reduction suggest marked therapeutic activity of PT-112 in bone metastases, likely a consequence of osteotropism conferred by the drug’s pyrophosphate moiety. Serologic and RECIST-defined responses, as well as prolonged disease control in multiple patients substantiate further development of PT-112 in mCRPC, as a monotherapy and in combination with immune checkpoint inhibition.
The poster #D7, abstract number 83, entitled, "PT-112 in advanced metastatic castrate-resistant prostate cancer (mCRPC), as monotherapy or in combination with PD-L1 inhibitor avelumab: Findings from two phase I studies," available here, will be presented by Alan H. Bryce, MD, Associate Professor of Medicine and Chair, Division of Hematology and Medical Oncology, Mayo Clinic, on Thursday, February 13, 2020 from 11:30 AM – 1:00 PM and 5:30 PM – 6:30 PM PST at the Genitourinary Cancers Symposium in San Francisco.
Phosplatin Therapeutics entered a clinical trial collaboration and supply agreement with Pfizer and Merck KGaA, Darmstadt, Germany, in 2017 to evaluate PT-112, a novel small molecule inducer of immunogenic cell death (ICD) in combination with avelumab*, a human anti-PD-L1 IgG1 monoclonal antibody.
Further information on these clinical trials that are currently open can be found at the clinicaltrials.gov registry under NCT 02266745 and NCT 03409458.
*Avelumab is under clinical investigation for treatment of solid tumors in combination with PT-112. There is no guarantee that avelumab will be approved for use in prostate cancer by any health authority.
About PT-112
PT-112 is a novel anti-cancer agent, the first cytotoxic small molecule conjugate of pyrophosphate developed in oncology therapeutics. PT-112 promotes immunogenic cell death (ICD), or the release of damage associated molecular patterns (DAMPs) that lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a potential best-in-class small molecule inducer of this immunological form of cancer cell death. The first-in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses and tumor control among heavily pre-treated patients, and was presented at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress, winning "Best Poster" among the Developmental Therapeutics category. The novelty of its pyrophosphate moiety also results in osteotropism, or the propensity of the drug to reach the mineralized bone. This property is of interest in cancer types with metastatic bone involvement, such as mCRPC.
Avelumab Approved Indications
Avelumab (BAVENCIO) in combination with axitinib is indicated in the US, EU, Japan and other countries for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
The US Food and Drug Administration (FDA) also granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Avelumab is currently approved for patients with mMCC in 50 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.
Avelumab Important Safety Information from the US FDA-Approved Label
The warnings and precautions for avelumab (BAVENCIO) include immune-mediated adverse reactions (such as pneumonitis and hepatitis [including fatal cases], colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions [which can be severe and have included fatal cases]), infusion-related reactions, hepatotoxicity, major adverse cardiovascular events (MACE) [which can be severe and have included fatal cases], and embryo-fetal toxicity.
Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO monotherapy include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash. Common adverse reactions (reported in at least 20% of patients) in patients receiving BAVENCIO in combination with axitinib include diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain and headache. Grade 3-4 clinical chemistry and hematology laboratory value abnormalities reported in at least 10% of patients treated with BAVENCIO monotherapy include hyponatremia, lymphopenia, GGT increased; in patients receiving BAVENCIO in combination with axitinib, grade 3-4 clinical chemistry and hematology laboratory value abnormalities included blood triglyceride increased and lipase increased.