Ignite Creation Date:
2024-05-06 @ 3:54 AM
Last Modification Date:
2024-10-26 @ 11:41 AM
Study NCT ID:
NCT02407080
Status:
COMPLETED
Last Update Posted:
2019-09-12
First Post:
2015-03-24
Brief Title:
Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia
Sponsor:
John Mascarenhas
Organization:
Icahn School of Medicine at Mount Sinai
Study Overview
Official Title:
Open Label Phase I Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia With Pilot Feasibility Study in Combination With Pegylated Interferon Alfa 2a for Patients Who do Not Respond to the Single Agent at Each Dose Level
Status:
COMPLETED
Status Verified Date:
2019-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This research looks at two conditions Essential Thrombocythemia ET and Polycythemia Vera PV ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising Having too many platelets in the blood increases the risk of developing blood clots which can result in life threatening events like heart attacks and strokes When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increase the risk of developing blood clots
The purpose of Part A of this study is to test the safety and tolerability of drug RG7388 patients and identify the recommended phase II dose in a single agent dose escalation study The investigators want to find out what effects good andor bad it has on the disease
The purpose of Part B of this study is to test the safety and tolerability of the combination of RG7388 and Pegylated Interferon Alfa-2a or Pegasys in PVET patients from Part A who did not achieve at least a partial response by the end of three cycles of single agent RG7388
Essential Thrombocythemia ET and Polycythemia Vera PV have been difficult diseases to treat RG7388 is a selective inhibitor of the p53-MDM2 binding that frees p53 from negative control and activates the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis in vitro and in vivo It has been used to treat solid tumors and Acute Myelogenous Leukemia AML in clinical trials Pegasys is a drug that is the standard of care for patients who have Chronic Hepatitis B CHB
RG7388 is a drug that is not yet approved by the Federal Drug Administration FDA for the treatment of patients with essential thrombocythemia or polycythemia vera Pegasys is a drug that is approved by the FDA for the treatment of CHB The use of RG7388 alone and in combination with Pegasys is experimental
The purpose of Part A of this study is to test the safety and tolerability of drug RG7388 patients and identify the recommended phase II dose in a single agent dose escalation study The investigators want to find out what effects good andor bad it has on the disease
The purpose of Part B of this study is to test the safety and tolerability of the combination of RG7388 and Pegylated Interferon Alfa-2a or Pegasys in PVET patients from Part A who did not achieve at least a partial response by the end of three cycles of single agent RG7388
Essential Thrombocythemia ET and Polycythemia Vera PV have been difficult diseases to treat RG7388 is a selective inhibitor of the p53-MDM2 binding that frees p53 from negative control and activates the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis in vitro and in vivo It has been used to treat solid tumors and Acute Myelogenous Leukemia AML in clinical trials Pegasys is a drug that is the standard of care for patients who have Chronic Hepatitis B CHB
RG7388 is a drug that is not yet approved by the Federal Drug Administration FDA for the treatment of patients with essential thrombocythemia or polycythemia vera Pegasys is a drug that is approved by the FDA for the treatment of CHB The use of RG7388 alone and in combination with Pegasys is experimental
Detailed Description:
The Philadelphia chromosome-negative chronic myeloproliferative neoplasms MPNs are a group of hematopoietic stem cell malignancies that include polycythemia vera PV essential thrombocythemia ET and primary myelofibrosis PMF PV and ET can evolve into myelofibrosis termed post PVET MF ET PV and PMF have variable tendencies to transform to blast phase disease with a dismal prognosis JAK2V617F is a point activating mutation resulting in the constitutive activity of the JAK-STAT pathway within hematopoietic cells in approximately 96 50 and 50 of patients with PV ET and MF respectively
Polycythemia Vera is characterized by an absolute increase in red cell mass Patients with PV have a median survival if untreated of approximately 18 months from the time of diagnosis and treated of approximately 18 years PV-related symptoms include headache weakness dizziness epigastric distress and pruritus PV-related signs include hypertension gout left upper abdominal quadrant pain high hematocrit leukocytosis and thrombocytosis Major causes of reduced survival include thrombosis 29 bleeding 7 evolution to myelofibrosis 3 transformation to acute leukemia 23 and solid tumors 16 PV patients are stratified for risk of thrombosis by age 60 and history of prior thrombotic events Therapy for low risk PV includes low dose aspirin and therapeutic phlebotomy to maintain a hematocrit 45 in a man and 42 in a woman Cardiovascular risk factor modification such as weight loss control of hypertension and hypercholesterolemia and smoking cessation are also important adjunctive approaches to all patients with PV High risk patients are also treated with cytoreductive therapy in the form of hydroxyurea to further reduce the risk of thrombotic complications
Essential Thrombocythemia is characterized by persistent isolated thrombocytosis and tendency for arterial and venous thrombosis A similar pattern of symptoms as noted above with PV are also seen in patients with ET The median survival of patients with ET is similar to that of age and sex matched cohort and in some patients is limited by thrombotic complications 22 evolution to MF 10 and acute leukemia 2 Barbui J Clin Oncol 2011 29233179 Risk stratification for occurrence of thrombosis is based on age 60 years andor history of thrombosis Additionally cardiovascular risk factors and persistent thrombocytosis 15 x 109L are believed to influence thrombotic risk and leukemic transformation has been shown to be associated with anemia older age and leukocytosis JAK2V617F is present in approximately 50 of cases and helps establish a diagnosis of a clonal thrombocytosis and has been shown in some studies to predict for a higher risk of thrombosis and potential for transformation to PV Management is aimed at reducing thrombotic risk with the use of low dose aspirin in low risk patients no risk factors and cytoreductive therapy in high risk patients at least one risk factor Hydroxyurea anagrelide and interferon IFN have all been used to maintain a platelet count below 400 x 109L in patients with a history of thrombosis secondary prophylaxis Currently hydroxyurea is considered standard of care for high risk ET patients based on the results of the PT-1 study which demonstrated superiority of hydroxyurea over anagrelide in arterial thrombosis risk reduction and worsening marrow reticulin fibrosis in patients receiving anagrelide Harrison N Engl J Med 2005353133 Hydroxyurea is associated with a risk of oral and skin ulcers rash and unacceptable myelosuppression that can sometimes limit use in patients with ETPV Additionally some patients are unable to achieve adequate control of blood counts at doses below 2000 mgdaily and this has been termed resistance Importantly although a theoretical concern of leukemogenic potential of hydroxyurea exists based on the mechanism of action of this chemotherapeutic agent there are no definitive prospective studies clearly documenting an increased risk of leukemic transformation
More recently a renewed interest in interferon-α for the treatment of PV as an alternative therapeutic approach has led to the evaluation of pegylated interferon-α 2a Pegasys Roche in several phase II studies Pegasys has an improved toxicity profile over intron-a and can be self-administered by the patient on a weekly basis Currently Pegasys is being evaluated in two large international trials within the myeloproliferative disorder research consortium MPD-RC The MPD-RC 111 study is a phase II study intended to evaluate the response by European LeukemiaNet ELN criteria in patients with high risk ETPV who are intolerant or resistant to hydroxyurea therapy treated with Pegasys In addition patients with documented JAK2V617F and splanchnic vein thrombosis are also eligible for this clinical trial MPD-RC 112 is a phase III study for newly diagnosed high risk PVET patients in which patients are randomized to either Pegasys or hydroxyurea with a primary endpoint of response rate comparison between the two treatment arms
The use of intron-a rIFN-α and Pegasys has been extensively studied in patients with PV and reported rates of discontinuation in the first year of therapy range from 14-40 Objective hematologic responses are seen in approximately 80 of treated patients and achievement in complete phlebotomy free state in 60 of PV patients Trials of Pegasys in the treatment of PV have further demonstrated major molecular responses of 19 and complete eradication of JAK2V617F in 14-24 of patients Although hematologic remission can often be achieved within months of starting rIFN-α treatment molecular responses require longer term administration and are rarely seen before completion of 12 months of therapy Additionally sustained molecular remissions have been documented in patients that have discontinued therapy for up to 30 months of follow up In a retrospective review of 118 MPN patients receiving Pegasys throughout multiple MPN centers included 55 PV patients with an ORR of 87 54 CR 33 PR by ELN criteria 21 In this review the most common non-hematologic toxicities were Grade 1-3 fatigue in 24 patients 20 Grade 1 liver function test LFT elevation in 7 6 and Grade 1-2 skinallergic reaction in 6 5 Adverse effects leading to discontinuation were primarily non-hematologic although one patient 1 discontinued Pegasys therapy due to Grade 2 anemia
Although the biological mechanism of recombinant IFN in the treatment of PV is not completely understood evidence to suggest promotion of immunoregulatory cell function inhibition of angiogenesis induction of pro-apoptotic gene expression alteration of the bone marrow microenvironment suppression of hematopoietic progenitor cells and increase cycling of hematopoietic stem cells HSC has been reported
In the last several years oral small molecule tyrosine kinase inhibitors of JAK2 have been tested in both pre-clinical and clinical trials of patients with MPNs including PVET These agents have demonstrated remarkable responses in terms of reduction in splenomegaly and correction of leukocytosis erythrocytosis and thrombocytosis However mature follow up of PV patients treated with JAK2 inhibitors evaluating reduction in thrombotic risk and evolution to MF is not known Currently Ruxolitinib Jakafi is being evaluated in a phase III study in patients with high risk PV that are refractoryintolerant to hydroxyurea Response trial NCT01243944
The tumor suppressor p53 plays an integral role in the regulation of the cell cycle apoptosis DNA repair and senescence Fifty percent of cancers are found to have inactivating mutations of p53 Although inactivating mutations of p53 are uncommon in the chronic phases of MPNs they increase in frequency in the blast phase of MPNs The p53 pathway can also be down-regulated in MPN cells that express wild-type p53 through alternative pathways Over-expression of the ubiquitin ligase murine double minute 2 MDM2 HDM2 in humans is a regulator of wild type p53 through a variety of different mechanisms MDM2 1 promotes proteosomal degradation and 2 inhibits p53 transcription and 3 inhibits transactivation 4 facilitates export from the nucleus Inhibition of MDM2 is expected to release the negative regulation of p53 and ultimately promote tumor suppressor function MDM2 overexpression can be a consequence of gene amplification increased transcription and increased translation It has previously been shown that in primary hematopoietic cells from patients with JAK2V617F PV reduced expression of p53 is a result of increased La autoantigen expression leading to increased translation of MDM2 It would appear that JAK2V617F induces this ribonucleoprotein and furthermore La protein expression can be down-regulated by in vitro JAK2 inhibitor treatment Lu et al demonstrated increased MDM2 expression and reduced p53 levels in JAK2V617F-positive PV CD34 cells The physical structure and interaction of p53 and MDM2 is known and has allowed for the development of small molecule inhibitors of MDM2-p53 interaction Nutlin-3 a small molecule antagonist of MDM2 was shown to inhibit the proliferation of PV CD34 cells through increased p53 mediated apoptosis Moreover in vitro combination of low doses of Pegasys with nutlin-3 resulted in selective and significant inhibition of JAK2V67F-positive CD34 PV colony formation compared to normal colony formation Thus MDM2 appears to be a novel therapeutic target in JAK2V617F-positive PV and ultimately may prove to be most effective when used in combination with Pegasys
RG7388 is an MDM2-p53 binding cell cycle inhibitor antiproliferative and is expected to be myelosuppressive at sufficiently high doses Nonclinical safety findings with RG7388 that may have potential clinical relevance include thrombocytopenia and neutropenia as well as general pancytopenia and effects on liver function parameters
Clinical experience to date suggests a dose relationship for RG7388 and gastrointestinal AEs with increased incidence of nausea vomiting and diarrhea at higher dose levels gastrointestinal prophylaxis with anti-emetics is recommended Cytopenias manifesting as thrombocytopenia and neutropenia occurring at higher dose levels appear to be related to exposure
Iancu-Rubin et al have investigated the biological effect of RG7112 first generation MDM2 inhibitor induced p53-MDM2 disruption on megakaryopoiesis and platelet production in order to better elucidate the mechanism of treatment associated thrombocytopenia ASH 2012 Bone marrow derived CD34 cells exposed to RG7112 for 7 days generated fewer viable cells fewer CFU-MK colonies as compared to untreated cells Based on these findings it would appear that RG7112 impacts megakaryopoiesis by two potential mechanisms 1 Impairing the ability of CD34 cells to generate MK precursors due to increased apoptosis 2 Limiting DNA synthesis and polyploidization during the late stages of MK development due to pharmacological activation of p53 A combination of these two effects may provide an explanation for thrombocytopenia observed in patients receiving this drug and suggests that p53 plays an important role in normal human thrombocytopoiesis
Study NP27872 is a multi-center open-label first-in-human Phase I dose-escalation study of single agent RG7388 a small molecule MDM2 antagonist administered orally in patients with advanced malignancies except leukemia The first patient received RG7388 on 15 November 2011 As of 13 September 2012 51 patients have been enrolled in the study
Evaluable PK data is available for 22 patients in Study NP27872 There has been no evidence of significant accumulation defined as a mean ratio of area under the curve AUCτ on Day 15 or 5 to AUCinf on Day 1 2 observed in the study thus far except for one patient who exhibited a long half-life t½ and consequently had an accumulated drug exposure that increased 5-fold from Day 1 to Day 5 This was possibly due to concomitant controlled-release oxycodone as opioids are known to cause delayed gastric emptying and decreased intestinal motility In addition data from the study demonstrate an approximately linear dose-exposure Day 1 maximum plasma concentration Cmax relationship in RG7388 with moderately high inter-patient variability without an absorption plateau to date
Macrophage inhibitory cytokine MIC-1 a secreted protein that is strongly induced by activated p53 serum levels has been used to assess pharmacodynamic PD effects in this Phase I study Analysis of patients on 100 to 800 mgday of RG7388 showed that the minimum level for p53 induction occurs at a dose of 100 mgday or a corresponding plasma level of 500 ngmL of RG7388 Preliminary analysis of PK and safety data showed that there is an apparent PKPD relationship between an AUC per cycle and Cycle 1 platelet nadir
At the data cutoff of 13 September 2012 51 patients with advanced malignancies had received R05503781 in Study NP27872 Fifty patients experienced at least 1 adverse event AE and 11 patients experienced at least 1 serious adverse event SAE
Thirteen SAEs in patients white blood cell count decreased platelet count decreased 2 cases of neutrophil count decreased febrile neutropenia 5 cases of thrombocytopenia 2 cases of neutropenia and diarrhea were considered by the investigator to be probably related to study treatment 4 SAEs 2 cases of febrile neutropenia urinary tract infection and anemia were considered possibly related 1 SAE lung infection was considered remotely related and the other 6 SAEs infection sciatica non-cardiac chest pain dyspnea wrist fracture and neutropenia were considered unrelated Three patients died due to disease progression
Eleven patients across all groups and schedules had at least 1 event considered a dose limiting toxicity DLT a treatment-related SAE of Grade 3 febrile neutropenia a treatment-related SAE of Grade 4 febrile neutropenia a treatment-related SAE of Grade 4 platelet count decreased 3 cases of treatment-related SAEs of Grade 4 thrombocytopenia a treatment-related AE of Grade 4 thrombocytopenia 3 cases of treatment-related AEs of Grade 4 thrombocytopenia a treatment-related AE of Grade 4 neutropenia a treatment-related SAE of Grade 4 neutropenia a treatment-related AE of Grade 3 diarrhea 2 cases of treatment-related AEs of Grade 3 nausea and a treatment related AE of Grade 3 vomiting Six patients experienced 8 AEs that led to withdrawal from treatment 1 Grade 3 AE of cataracts was considered remotely related to study treatment 4 Grade 4 AE of thrombocytopeniaGrade 3 SAE of febrile neutropenia Grade 2 AE of neutropenia Grade 3 SAE of febrile neutropenia were considered possibly related to study treatment and 3 Grade 4 SAE of neutropenia Grade 4 SAE of thrombocytopeniaGrade 4 SAE of neutrophil count decreased were considered probably related to study treatment
RG7388 is representative of an entirely new branch of the nutlin family of MDM2 antagonists and the second agent with this mechanism of action sponsored by Roche As with the lead compound RO5045337 RG7388 binds selectively to the p53 site on the surface of the MDM2 molecule in vitro with high affinity and can effectively displace p53 from MDM2 leading to stabilization and accumulation of p53 protein and activation of the p53 pathway RG7388 is from a different chemical series compared to the lead compound and binds with higher potency and selectivity to the MDM2 protein This follow-on compound has substantially improved pharmacological properties Preclinical models predict superior efficacy of RG7388 in the clinic at lower doses and exposures Compared to the lead molecule lower variability may be seen given that RG7388 does not have significant pH dependent solubility fasted and fed-state simulated intestinal fluid solubilities are similar RG7388 at 03 μM has equivalent apoptotic activity to RO5045337 at 10-fold higher 3 μM concentration and at 25 mgkg has equivalent efficacy to RO5045337 at 4-fold higher dose 100 mgkg and better potency when given once weekly
RG7388 exhibits improved in vitro and in vivo potency against tumor cell lines and xenografts improved CYP inhibition profile and 25- to 20-fold lower projected human efficacious dose Preclinical studies have indicated that tumors expressing wild-type p53 may respond to this novel therapeutic strategy that releases p53 from MDM2 inhibition and tumors with wild-type p53 and MDM2 over-expression or amplification are likely to be the most sensitive Results from preclinical safety and toxicology studies support further exploration of this compound in cancer patients In view of the existing unmet medical need in advanced cancers expressing the above molecular signature RG7388 is believed to be a promising agent that may offer a new therapeutic option
The use of Pegasys in combination with other targeted agents for the treatment of PVET would allow for the administration of lower doses of Pegasys thereby reducing dose dependent toxicities Preclinical studies by Lu et al have demonstrated preferential inhibition of PV CD34 cell proliferation and colony formation at subtherapeutic doses of Pegasys in combination with Nutlin-3 33 Pegasys increases p53 expression through enhanced transcriptional activity via the p38 Map kinase pathway and Nutlin-3 prevents p53 degradation via interruption of the MDM2-p53 interaction 34 Due to the common downstream target effect of increased tumor suppressor p53 expression with combination Pegasys and Nutlin-3 lower doses of each agent can be used together in PV patients Thus the use of RG7388 alone or in combination with Pegasys would be anticipated to enhance p53 expression by different mechanisms and presents a novel approach to the treatment of PVET
Polycythemia Vera is characterized by an absolute increase in red cell mass Patients with PV have a median survival if untreated of approximately 18 months from the time of diagnosis and treated of approximately 18 years PV-related symptoms include headache weakness dizziness epigastric distress and pruritus PV-related signs include hypertension gout left upper abdominal quadrant pain high hematocrit leukocytosis and thrombocytosis Major causes of reduced survival include thrombosis 29 bleeding 7 evolution to myelofibrosis 3 transformation to acute leukemia 23 and solid tumors 16 PV patients are stratified for risk of thrombosis by age 60 and history of prior thrombotic events Therapy for low risk PV includes low dose aspirin and therapeutic phlebotomy to maintain a hematocrit 45 in a man and 42 in a woman Cardiovascular risk factor modification such as weight loss control of hypertension and hypercholesterolemia and smoking cessation are also important adjunctive approaches to all patients with PV High risk patients are also treated with cytoreductive therapy in the form of hydroxyurea to further reduce the risk of thrombotic complications
Essential Thrombocythemia is characterized by persistent isolated thrombocytosis and tendency for arterial and venous thrombosis A similar pattern of symptoms as noted above with PV are also seen in patients with ET The median survival of patients with ET is similar to that of age and sex matched cohort and in some patients is limited by thrombotic complications 22 evolution to MF 10 and acute leukemia 2 Barbui J Clin Oncol 2011 29233179 Risk stratification for occurrence of thrombosis is based on age 60 years andor history of thrombosis Additionally cardiovascular risk factors and persistent thrombocytosis 15 x 109L are believed to influence thrombotic risk and leukemic transformation has been shown to be associated with anemia older age and leukocytosis JAK2V617F is present in approximately 50 of cases and helps establish a diagnosis of a clonal thrombocytosis and has been shown in some studies to predict for a higher risk of thrombosis and potential for transformation to PV Management is aimed at reducing thrombotic risk with the use of low dose aspirin in low risk patients no risk factors and cytoreductive therapy in high risk patients at least one risk factor Hydroxyurea anagrelide and interferon IFN have all been used to maintain a platelet count below 400 x 109L in patients with a history of thrombosis secondary prophylaxis Currently hydroxyurea is considered standard of care for high risk ET patients based on the results of the PT-1 study which demonstrated superiority of hydroxyurea over anagrelide in arterial thrombosis risk reduction and worsening marrow reticulin fibrosis in patients receiving anagrelide Harrison N Engl J Med 2005353133 Hydroxyurea is associated with a risk of oral and skin ulcers rash and unacceptable myelosuppression that can sometimes limit use in patients with ETPV Additionally some patients are unable to achieve adequate control of blood counts at doses below 2000 mgdaily and this has been termed resistance Importantly although a theoretical concern of leukemogenic potential of hydroxyurea exists based on the mechanism of action of this chemotherapeutic agent there are no definitive prospective studies clearly documenting an increased risk of leukemic transformation
More recently a renewed interest in interferon-α for the treatment of PV as an alternative therapeutic approach has led to the evaluation of pegylated interferon-α 2a Pegasys Roche in several phase II studies Pegasys has an improved toxicity profile over intron-a and can be self-administered by the patient on a weekly basis Currently Pegasys is being evaluated in two large international trials within the myeloproliferative disorder research consortium MPD-RC The MPD-RC 111 study is a phase II study intended to evaluate the response by European LeukemiaNet ELN criteria in patients with high risk ETPV who are intolerant or resistant to hydroxyurea therapy treated with Pegasys In addition patients with documented JAK2V617F and splanchnic vein thrombosis are also eligible for this clinical trial MPD-RC 112 is a phase III study for newly diagnosed high risk PVET patients in which patients are randomized to either Pegasys or hydroxyurea with a primary endpoint of response rate comparison between the two treatment arms
The use of intron-a rIFN-α and Pegasys has been extensively studied in patients with PV and reported rates of discontinuation in the first year of therapy range from 14-40 Objective hematologic responses are seen in approximately 80 of treated patients and achievement in complete phlebotomy free state in 60 of PV patients Trials of Pegasys in the treatment of PV have further demonstrated major molecular responses of 19 and complete eradication of JAK2V617F in 14-24 of patients Although hematologic remission can often be achieved within months of starting rIFN-α treatment molecular responses require longer term administration and are rarely seen before completion of 12 months of therapy Additionally sustained molecular remissions have been documented in patients that have discontinued therapy for up to 30 months of follow up In a retrospective review of 118 MPN patients receiving Pegasys throughout multiple MPN centers included 55 PV patients with an ORR of 87 54 CR 33 PR by ELN criteria 21 In this review the most common non-hematologic toxicities were Grade 1-3 fatigue in 24 patients 20 Grade 1 liver function test LFT elevation in 7 6 and Grade 1-2 skinallergic reaction in 6 5 Adverse effects leading to discontinuation were primarily non-hematologic although one patient 1 discontinued Pegasys therapy due to Grade 2 anemia
Although the biological mechanism of recombinant IFN in the treatment of PV is not completely understood evidence to suggest promotion of immunoregulatory cell function inhibition of angiogenesis induction of pro-apoptotic gene expression alteration of the bone marrow microenvironment suppression of hematopoietic progenitor cells and increase cycling of hematopoietic stem cells HSC has been reported
In the last several years oral small molecule tyrosine kinase inhibitors of JAK2 have been tested in both pre-clinical and clinical trials of patients with MPNs including PVET These agents have demonstrated remarkable responses in terms of reduction in splenomegaly and correction of leukocytosis erythrocytosis and thrombocytosis However mature follow up of PV patients treated with JAK2 inhibitors evaluating reduction in thrombotic risk and evolution to MF is not known Currently Ruxolitinib Jakafi is being evaluated in a phase III study in patients with high risk PV that are refractoryintolerant to hydroxyurea Response trial NCT01243944
The tumor suppressor p53 plays an integral role in the regulation of the cell cycle apoptosis DNA repair and senescence Fifty percent of cancers are found to have inactivating mutations of p53 Although inactivating mutations of p53 are uncommon in the chronic phases of MPNs they increase in frequency in the blast phase of MPNs The p53 pathway can also be down-regulated in MPN cells that express wild-type p53 through alternative pathways Over-expression of the ubiquitin ligase murine double minute 2 MDM2 HDM2 in humans is a regulator of wild type p53 through a variety of different mechanisms MDM2 1 promotes proteosomal degradation and 2 inhibits p53 transcription and 3 inhibits transactivation 4 facilitates export from the nucleus Inhibition of MDM2 is expected to release the negative regulation of p53 and ultimately promote tumor suppressor function MDM2 overexpression can be a consequence of gene amplification increased transcription and increased translation It has previously been shown that in primary hematopoietic cells from patients with JAK2V617F PV reduced expression of p53 is a result of increased La autoantigen expression leading to increased translation of MDM2 It would appear that JAK2V617F induces this ribonucleoprotein and furthermore La protein expression can be down-regulated by in vitro JAK2 inhibitor treatment Lu et al demonstrated increased MDM2 expression and reduced p53 levels in JAK2V617F-positive PV CD34 cells The physical structure and interaction of p53 and MDM2 is known and has allowed for the development of small molecule inhibitors of MDM2-p53 interaction Nutlin-3 a small molecule antagonist of MDM2 was shown to inhibit the proliferation of PV CD34 cells through increased p53 mediated apoptosis Moreover in vitro combination of low doses of Pegasys with nutlin-3 resulted in selective and significant inhibition of JAK2V67F-positive CD34 PV colony formation compared to normal colony formation Thus MDM2 appears to be a novel therapeutic target in JAK2V617F-positive PV and ultimately may prove to be most effective when used in combination with Pegasys
RG7388 is an MDM2-p53 binding cell cycle inhibitor antiproliferative and is expected to be myelosuppressive at sufficiently high doses Nonclinical safety findings with RG7388 that may have potential clinical relevance include thrombocytopenia and neutropenia as well as general pancytopenia and effects on liver function parameters
Clinical experience to date suggests a dose relationship for RG7388 and gastrointestinal AEs with increased incidence of nausea vomiting and diarrhea at higher dose levels gastrointestinal prophylaxis with anti-emetics is recommended Cytopenias manifesting as thrombocytopenia and neutropenia occurring at higher dose levels appear to be related to exposure
Iancu-Rubin et al have investigated the biological effect of RG7112 first generation MDM2 inhibitor induced p53-MDM2 disruption on megakaryopoiesis and platelet production in order to better elucidate the mechanism of treatment associated thrombocytopenia ASH 2012 Bone marrow derived CD34 cells exposed to RG7112 for 7 days generated fewer viable cells fewer CFU-MK colonies as compared to untreated cells Based on these findings it would appear that RG7112 impacts megakaryopoiesis by two potential mechanisms 1 Impairing the ability of CD34 cells to generate MK precursors due to increased apoptosis 2 Limiting DNA synthesis and polyploidization during the late stages of MK development due to pharmacological activation of p53 A combination of these two effects may provide an explanation for thrombocytopenia observed in patients receiving this drug and suggests that p53 plays an important role in normal human thrombocytopoiesis
Study NP27872 is a multi-center open-label first-in-human Phase I dose-escalation study of single agent RG7388 a small molecule MDM2 antagonist administered orally in patients with advanced malignancies except leukemia The first patient received RG7388 on 15 November 2011 As of 13 September 2012 51 patients have been enrolled in the study
Evaluable PK data is available for 22 patients in Study NP27872 There has been no evidence of significant accumulation defined as a mean ratio of area under the curve AUCτ on Day 15 or 5 to AUCinf on Day 1 2 observed in the study thus far except for one patient who exhibited a long half-life t½ and consequently had an accumulated drug exposure that increased 5-fold from Day 1 to Day 5 This was possibly due to concomitant controlled-release oxycodone as opioids are known to cause delayed gastric emptying and decreased intestinal motility In addition data from the study demonstrate an approximately linear dose-exposure Day 1 maximum plasma concentration Cmax relationship in RG7388 with moderately high inter-patient variability without an absorption plateau to date
Macrophage inhibitory cytokine MIC-1 a secreted protein that is strongly induced by activated p53 serum levels has been used to assess pharmacodynamic PD effects in this Phase I study Analysis of patients on 100 to 800 mgday of RG7388 showed that the minimum level for p53 induction occurs at a dose of 100 mgday or a corresponding plasma level of 500 ngmL of RG7388 Preliminary analysis of PK and safety data showed that there is an apparent PKPD relationship between an AUC per cycle and Cycle 1 platelet nadir
At the data cutoff of 13 September 2012 51 patients with advanced malignancies had received R05503781 in Study NP27872 Fifty patients experienced at least 1 adverse event AE and 11 patients experienced at least 1 serious adverse event SAE
Thirteen SAEs in patients white blood cell count decreased platelet count decreased 2 cases of neutrophil count decreased febrile neutropenia 5 cases of thrombocytopenia 2 cases of neutropenia and diarrhea were considered by the investigator to be probably related to study treatment 4 SAEs 2 cases of febrile neutropenia urinary tract infection and anemia were considered possibly related 1 SAE lung infection was considered remotely related and the other 6 SAEs infection sciatica non-cardiac chest pain dyspnea wrist fracture and neutropenia were considered unrelated Three patients died due to disease progression
Eleven patients across all groups and schedules had at least 1 event considered a dose limiting toxicity DLT a treatment-related SAE of Grade 3 febrile neutropenia a treatment-related SAE of Grade 4 febrile neutropenia a treatment-related SAE of Grade 4 platelet count decreased 3 cases of treatment-related SAEs of Grade 4 thrombocytopenia a treatment-related AE of Grade 4 thrombocytopenia 3 cases of treatment-related AEs of Grade 4 thrombocytopenia a treatment-related AE of Grade 4 neutropenia a treatment-related SAE of Grade 4 neutropenia a treatment-related AE of Grade 3 diarrhea 2 cases of treatment-related AEs of Grade 3 nausea and a treatment related AE of Grade 3 vomiting Six patients experienced 8 AEs that led to withdrawal from treatment 1 Grade 3 AE of cataracts was considered remotely related to study treatment 4 Grade 4 AE of thrombocytopeniaGrade 3 SAE of febrile neutropenia Grade 2 AE of neutropenia Grade 3 SAE of febrile neutropenia were considered possibly related to study treatment and 3 Grade 4 SAE of neutropenia Grade 4 SAE of thrombocytopeniaGrade 4 SAE of neutrophil count decreased were considered probably related to study treatment
RG7388 is representative of an entirely new branch of the nutlin family of MDM2 antagonists and the second agent with this mechanism of action sponsored by Roche As with the lead compound RO5045337 RG7388 binds selectively to the p53 site on the surface of the MDM2 molecule in vitro with high affinity and can effectively displace p53 from MDM2 leading to stabilization and accumulation of p53 protein and activation of the p53 pathway RG7388 is from a different chemical series compared to the lead compound and binds with higher potency and selectivity to the MDM2 protein This follow-on compound has substantially improved pharmacological properties Preclinical models predict superior efficacy of RG7388 in the clinic at lower doses and exposures Compared to the lead molecule lower variability may be seen given that RG7388 does not have significant pH dependent solubility fasted and fed-state simulated intestinal fluid solubilities are similar RG7388 at 03 μM has equivalent apoptotic activity to RO5045337 at 10-fold higher 3 μM concentration and at 25 mgkg has equivalent efficacy to RO5045337 at 4-fold higher dose 100 mgkg and better potency when given once weekly
RG7388 exhibits improved in vitro and in vivo potency against tumor cell lines and xenografts improved CYP inhibition profile and 25- to 20-fold lower projected human efficacious dose Preclinical studies have indicated that tumors expressing wild-type p53 may respond to this novel therapeutic strategy that releases p53 from MDM2 inhibition and tumors with wild-type p53 and MDM2 over-expression or amplification are likely to be the most sensitive Results from preclinical safety and toxicology studies support further exploration of this compound in cancer patients In view of the existing unmet medical need in advanced cancers expressing the above molecular signature RG7388 is believed to be a promising agent that may offer a new therapeutic option
The use of Pegasys in combination with other targeted agents for the treatment of PVET would allow for the administration of lower doses of Pegasys thereby reducing dose dependent toxicities Preclinical studies by Lu et al have demonstrated preferential inhibition of PV CD34 cell proliferation and colony formation at subtherapeutic doses of Pegasys in combination with Nutlin-3 33 Pegasys increases p53 expression through enhanced transcriptional activity via the p38 Map kinase pathway and Nutlin-3 prevents p53 degradation via interruption of the MDM2-p53 interaction 34 Due to the common downstream target effect of increased tumor suppressor p53 expression with combination Pegasys and Nutlin-3 lower doses of each agent can be used together in PV patients Thus the use of RG7388 alone or in combination with Pegasys would be anticipated to enhance p53 expression by different mechanisms and presents a novel approach to the treatment of PVET
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| GCO 14-1919 | OTHER | Icahn School of Medicine at Mount Sinai | None |
| MPD-RC 115 | OTHER | None | None |