Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia
Information source: Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Polycythemia Vera; Essential Thrombocythemia
Intervention: RG7388 (Drug); Pegasys (Drug)
Phase: Phase 1
Status: Recruiting
Sponsored by: John Mascarenhas Official(s) and/or principal investigator(s): John Mascarenhas, MD, Study Chair, Affiliation: Icahn School of Medicine at Mount Sinai Ronald Hoffman, MD, Study Chair, Affiliation: Icahn School of Medicine at Mount Sinai
Overall contact: John Mascarenhas, MD, Phone: (212) 241-3417, Email: john.mascarenhas@mssm.edu
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 and/or 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 PV/ET 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.
Clinical Details
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)
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: The dose limiting toxicity of RG7388The dose limiting toxicity of combination of RG7388 and Pegasys
Secondary outcome: Hematologic response of PR + CR by modified ELN response criteriaMolecular response by percent reduction in baseline JAK2V617F allele burden Changes in bone marrow histopathologic abnormalities Reduction in baseline reticulin/collagen fibrosis Incidence of venous and arterial thrombosis Changes in MPN related symptoms as measured by the MPN-SAF
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 PV/ET 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; 29(23):3179). Risk stratification for occurrence of thrombosis is based on age >60
years and/or history of thrombosis. Additionally, cardiovascular risk factors and persistent
thrombocytosis >1. 5 x 109/L 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
109/L 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. 2005;353(1):33). Hydroxyurea is associated with a risk of
oral and skin ulcers, rash, and unacceptable myelosuppression that can sometimes limit use
in patients with ET/PV. Additionally, some patients are unable to achieve adequate control
of blood counts at doses below 2000 mg/daily 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 ET/PV 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 PV/ET 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 skin/allergic 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 PV/ET. 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 refractory/intolerant 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 [AUC]τ [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 mg/day of RG7388 showed that the minimum
level for p53 induction occurs at a dose of 100 mg/day or a corresponding plasma level of
500 ng/mL of RG7388. Preliminary analysis of PK and safety data showed that there is an
apparent PK/PD 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
thrombocytopenia/Grade 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 thrombocytopenia/Grade 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 0. 3 μM has
equivalent apoptotic activity to RO5045337 at 10-fold higher (3 μM) concentration and at 25
mg/kg has equivalent efficacy to RO5045337 at 4-fold higher dose (100 mg/kg) 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 2. 5- 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 PV/ET
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 PV/ET.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
(Patient should meet all the criteria)
- JAK2V617F-positive PV or JAK2V617F-positive ET (confirmed by WHO diagnostic criteria)
- High risk ET/PV [age >60; history of thrombosis] or low risk disease with symptoms
[recurrent headaches, paresthesias, pruritus]
- Previously treated with at least one other agent [hydroxyurea, interferon,
anagrelide] and determined to be either intolerant/resistant
- ≥18 years of age
- Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
- Acceptable pre-study organ function during screening as defined as: Total bilirubin ≤
1. 5 times the upper limit of normal (ULN) unless due to Gilbert's disease or
hemolysis, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2. 5
times ULN, Serum creatinine ≤ 1. 5 x ULN
- Women of childbearing potential and males must agree to use adequate contraception
(i. e., hormonal or barrier method of birth control; abstinence) prior to study entry
and for the duration of study participation. Should a female subject become pregnant
or suspect she is pregnant while participating in this study, she should inform the
treating physician immediately
- Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
- Meets the criteria for post ET/PV MF as defined by the International Working
Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
- Blast phase disease (>20% blasts in the marrow or peripheral blood)
- Acute thrombosis within 3 months of screening
- Uncontrolled intercurrent illness including, but not limited to hepatitis, human
immunodeficiency virus (HIV) - positive subjects receiving combination antiretroviral
therapy, ongoing or active infection, symptomatic congestive heart failure, unstable
angina pectoris, ventricular arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements.
Locations and Contacts
John Mascarenhas, MD, Phone: (212) 241-3417, Email: john.mascarenhas@mssm.edu
Mayo Clinic, Scottsdale, Arizona 85259, United States; Not yet recruiting Ruben Mesa, MD, Phone: 480-301-8335, Email: mesa.ruben@mayo.edu Ruben Mesa, MD, Principal Investigator
Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States; Recruiting John Mascarenhas, MD, Phone: 212-241-3417, Email: john.mascarenhas@mssm.edu Jill Kleczko, Phone: (212) 241-0573, Email: jill.kleczko@mssm.edu John Mascarenhas, MD, Principal Investigator
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Not yet recruiting Raajit Rampal, MD, PhD, Phone: 212-639-2194, Email: rampalr@mskcc.org Raajit Rampal, MD, Principal Investigator
Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, United States; Not yet recruiting Dmitry Berenzon, MD, Phone: 336-716-5847, Email: dberenzo@wfubmc.edu Dmitry Berenzon, MD, Principal Investigator
University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting Elizabeth Hexner, MD, Phone: 215-662-4137, Email: elizabeth.hexner@uphs.upenn.edu Elizabeth Hexner, MD, Principal Investigator
University of Utah, Salt Lake City, Utah 84132, United States; Not yet recruiting Josef Prchal, MD, Phone: 801-581-4220, Email: Josef.Prchal@hsc.utah.edu Josef Prchal, MD, Principal Investigator
Additional Information
Starting date: April 2015
Last updated: April 16, 2015
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