PF-06835375 for Low Platelet Count
Recruiting in Palo Alto (17 mi)
+34 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Pfizer
Disqualifiers: Recent bleeding, Splenectomy, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial uses a new injectable medicine called PF-06835375. It targets adults with long-lasting or chronic low platelet counts due to primary immune thrombocytopenia (ITP). The medicine works by reducing specific immune cells to help increase platelet counts.
Do I need to stop my current medications for this trial?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.
What evidence supports the effectiveness of the drug PF-06835375 for low platelet count?
The research mentions that thrombopoietin and its analogues, which are similar to PF-06835375, have been shown to be potent stimulators of platelet production and can enhance platelet recovery after chemotherapy. Additionally, other thrombopoietin receptor agonists like romiplostim and avatrombopag have been effective in increasing platelet counts in patients with immune thrombocytopenia.
12345Eligibility Criteria
This trial is for adults with primary immune thrombocytopenia (ITP) who have had low platelet counts for more than 3 months. They shouldn't have had severe bleeding in the last month or need blood products during screening, and they can't join if they've had a splenectomy within the past 3 months or plan to have one.Inclusion Criteria
I have been diagnosed with ITP and my platelet count is below 50, without severe bleeding in the last month.
Exclusion Criteria
I have had a significant bleeding event recently or need treatment for current bleeding.
I have had my spleen removed recently or will have it removed soon.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive subcutaneous injections of PF-06835375 once monthly. Cohort 1 receives treatment for 3 months, while cohorts 2 and 3 receive treatment for 4 months.
12-16 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment, focusing on changes in platelet counts.
4 weeks
Participant Groups
The study tests PF-06835375 through multiple subcutaneous injections to see if it's safe and effective for treating ITP. It's an open-label Phase 2 trial, meaning both researchers and participants know what treatment is being given.
3Treatment groups
Experimental Treatment
Group I: Open Label PF-06835375 dose 3 TreatmentExperimental Treatment1 Intervention
subcutaneous injection once monthly for 4 months
Group II: Open Label PF-06835375 dose 2 TreatmentExperimental Treatment1 Intervention
subcutaneous injection once monthly for 4 months
Group III: Open Label PF-06835375 dose 1 TreatmentExperimental Treatment1 Intervention
subcutaneous injection once monthly for 3 months
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
American Oncology Partners of Maryland, PABethesda, MD
East Carolina UniversityGreenville, NC
American Oncology Partners of MD, PABethesda, MD
Unity Health Toronto, St. Michael's HospitalToronto, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
PfizerLead Sponsor
References
Clinical biology and potential use of thrombopoietin. [2019]The discovery of platelet growth factors raised expectations that an effective method for abrogating thrombocytopenia would soon be available in the clinic. The cytokines initially described were pleiotropic in nature, and stimulation of platelet production was generally modest. However, one of these agents, interleukin-11, was successfully shown to reduce the incidence of severe thrombocytopenia in patients receiving dose-intensive chemotherapy, and has now received approval from the United States Food and Drug Administration for this purpose. Initial clinical trials of thrombopoietin, the central regulator of megakaryocytopoiesis and thrombopoiesis, and its analogues showed these agents to be the most potent stimulators of thrombopoiesis and to be associated with few adverse effects. They have also been shown to enhance platelet recovery after chemotherapy, but early results from trials investigating their ability to prevent severe thrombocytopenia associated with the treatment of leukemia and bone marrow transplantation have been disappointing. In addition, subcutaneous administration of one of these agents, megakaryocyte growth and development factor, has been shown to induce the formation of antibodies that neutralize native thrombopoietin and cause thrombocytopenia. Platelet growth factors remain promising therapeutic agents; however, there are a number of obstacles to overcome before they find general use in the clinic.
Romiplostim or standard of care in patients with immune thrombocytopenia. [2016]Romiplostim, a thrombopoietin mimetic, increases platelet counts in patients with immune thrombocytopenia, with few adverse effects.
Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. [2019]Avatrombopag, an oral thrombopoietin receptor agonist, was compared with placebo in a 6-month, multicentre, randomised, double-blind, parallel-group Phase 3 study, with an open-label extension phase, to assess the efficacy and safety of avatrombopag (20 mg/day) in adults with chronic immune thrombocytopenia (ITP) and a platelet count <30 × 109 /l (ClinicalTrials.gov identifier NCT01438840). The primary endpoint was the cumulative number of weeks of platelet response (platelet count ≥50 × 109 /l) without rescue therapy for bleeding; secondary endpoints included platelet response rate at day 8 and reductions in the use of concomitant medications. Amongst the 49 patients randomised, avatrombopag (N = 32) was superior to placebo (N = 17) in the median cumulative number of weeks of platelet response (12·4 vs. 0·0 weeks, respectively; P < 0·0001). At day 8, a greater platelet response rate was also observed for patients treated with avatrombopag compared with placebo (65·63% vs. 0·0%; P < 0·0001), and use of concomitant ITP medications was also reduced amongst patients receiving avatrombopag. The safety profile of avatrombopag was consistent with Phase 2 studies; the most common adverse events were headache and contusion. Overall, avatrombopag was well tolerated and efficacious for the treatment of chronic ITP.
Opportunities for the use of thrombopoietic growth factors. [2005]Highly lineage specific thrombopoietic factors are now available which can produce substantial increments in platelet counts and attenuate the severity of therapy induced thrombocytopenia in preclinical models and early trials in patients. These striking findings are not equivalent to proving clinical benefit to patients, however, and studies are now in progress in a variety of clinical settings. Methodologic issues which could influence the interpretation of studies using thrombopoietin to mitigate thrombocytopenia in patients treated for acute myeloid leukemia and following stem cell transplantation are discussed. Studies in thrombocytopenic patients with myelodysplasia, aplastic anemia, immune thrombocytopenic purpura, as well as selected platelet and stem cell donors, are also of interest. It is unclear, however, whether patients with impaired marrow function can benefit from further exogenous stimulation, and side effects must be very carefully monitored in studies with normal donors.
Chronic immune thrombocytopenic purpura. New agents. [2016]First generation thrombopoietic growth factors (rhTPO and PEG-rHuMGDF), investigated in the early 2000s, proved effective in increasing platelet count in normal volunteers, in thrombocytopenia due to chemotherapy and also in a few cases of immune thrombocytopenic purpura (ITP). These agents did not complete their clinical development since one of them induced antibodies in the recipients that cross reacted with endogenous thrombopoietin (TPO), thus causing thrombocytopenia. This promoted the ingenious design of a new generation of thrombopoietic growth factors having no sequence homology with natural TPO. The two main agents are romiplostim, a peptibody already approved for clinical use in USA and eltrombopag, a non-peptide, orally active small molecule. In open label and placebo-controlled trials both agents proved to predictably increase platelet count in normal volunteers and in patients with ITP. With appropriate dosages (1-10 microg/kg weekly sub cutaneously for romiplostim; 50-75 mg/die per os for eltrombopag ) a platelet increase becomes significant after 7-10 days and peaks between 10-14 days. By discontinuing treatment, platelet count returns to baseline level in 10-15 days. The response rate with both agents is above 70-80%, also in patients that had undergone several lines of treatment, or that have failed splenectomy. The response is maintained during the treatment, but is almost invariably lost even after several months of successful administration. Due to the lack of a curative potential and to the incomplete knowledge of long-term side effects, the place of these new drugs in the management of ITP is still unsettled and their use is best restricted to refractory patients or in preparation of splenectomy. It seems however that a new paradigm in the treatment of ITP has been established where the focus is not on reducing platelet consumption but on increasing platelet production.
Intravenous and oral antiplatelet/antithrombotic efficacy and specificity of XR300, a novel nonpeptide platelet GPIIb/IIIa antagonist. [2019]Currently used antiplatelet drugs including aspirin, ticlopidine, and others are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus our study was undertaken to define the antiplatelet efficacy, specificity, and the intravenous and oral antiplatelet/antithrombotic effects of a nonpeptide glycoprotein alphaIIb beta3 integrin (GPIIb/IIIa) antagonist XR300, an ethyl ester prodrug of XR299. XR300, on its conversion to the active form XR299, inhibited human platelet aggregation induced by 100 microM adenosine diphosphate (ADP) with a median inhibitory concentration (IC50) of 0.09 microM. Similarly, XR299 inhibited 125I-fibrinogen binding to human gel-purified platelets (IC50, 0.01 microM) regardless of the agonist used. In purified human GPIIb/IIIa, XR299 demonstrated a competitive high-affinity binding with an IC50 of 1.2 nM. XR299 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alphaIIb beta3) as compared with other integrins including alpha(v)beta3, alpha(v)beta5, and alpha4beta1, where IC50 values were >10 microM. XR300 administered to mongrel dogs either intravenously (0.5-1.0 mg/kg, i.v.) or orally at 1.0-2.0 mg/kg, demonstrated maximal antiplatelet effects with rapid onset and extended duration. XR300 demonstrated maximal antithrombotic efficacy in preventing the incidence of occlusive thrombosis or cyclic flow reduction (CFR) in the carotid or femoral artery thrombosis models induced either electrolytically or by mechanical injury along with stenosis. In conclusion, XR300 is a novel intravenous and oral antiplatelet/antithrombotic agent with high affinity and specificity for platelet GPIIb/IIIa receptors.
Inhibition of platelet aggregation by a new agent, 2,2'-dithiobis-(N-2-hydroxypropyl benzamide) (KF4939). [2019]KF4939, 2,2'-dithiobis-(N-2-hydroxypropylbenzamide), is a potent inhibitor of platelet aggregation in vitro in rabbit and human PRP. This agent inhibited both cyclooxygenase product-dependent (collagen and arachidonate) and independent (ADP and thrombin)-platelet aggregations. This action carried over to ex vivo situation following intraduodenal dosing as demonstrated in rabbits. KF4939 inhibited experimentally induced thrombocytopenias in rats and pulmonary thrombosis in mice following oral doses in a range of 25-300mg/kg. These results indicate that KF4939 is a new orally active inhibitor of platelet aggregation possessing a different mode of action from cyclooxygenase inhibition.
The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760. [2003]The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)
Ex vivo effects of SR 27417, a novel PAF antagonist, on rabbit platelet aggregation and [3H]-PAF binding. [2017]Pharmacodynamics of SR 27417, a novel, specific platelet-activating factor (PAF) antagonist was monitored with ex vivo PAF-induced platelet aggregation in the rabbit. Single per os administration of SR 27417 (5 mg/kg) resulted in complete inhibition of this aggregation for at least 3 days. The magnitude of this inhibitory effect was dose-dependent with a maximum effect 1-3 h after oral administration. IC50 values for PAF-induced platelet aggregation were 80, 35, 50 and 1250 micrograms/kg, 1, 3, 24 and 72 h after oral intake of SR 27417 respectively. This effect was irreversible in nature since it could not be overcome by prolonged incubation of platelets isolated from treated animals in plasma from controls or in buffer. Examination of [3H]-PAF binding to washed platelets isolated 5 min after i.v. administration of increasing concentrations of SR 27417 revealed a competitive-type of inhibition whereas 24 h after p.o. administration, SR 27417 antagonized [3H]-PAF binding in a non-competitive manner.
CV3988 inhibits in vivo platelet aggregation induced by PAF-acether and collagen. [2019]Platelet activating factor (PAF-acether) was shown to cause a fall in the circulating platelet count and blood pressure (BP) in anaesthetised rabbits. CV3988 caused a dose-dependent inhibition of these responses to a low dose of PAF-acether (150 ng X kg-1). CV3988 itself was found to cause a fall in both BP and platelet count in vivo. Collagen (40 micrograms X kg-1) i.v. caused sudden death in rabbits and pretreatment with CV3988 (5 mg X kg-1) caused a 62% inhibition of the platelet count response to collagen without significantly increasing the survival rate. In the rat, collagen (40 micrograms X kg-1) was not lethal and CV3988 caused a dose-dependent inhibition of the fall in platelet count due to collagen, but this action was short-lived. CV3988 also caused agonist actions in the rat. These results show that CV3988 inhibits the effects of PAF-acether in vivo and suggests that PAF-acether may play a role in mediating collagen-induced platelet aggregation in vivo.