Study phase Phase I/II
Study objectives – To establish an effective dose of ruxolitinib and buparlisib combined in patients with primary myelofibrosis
– To assess the efficacy of ruxolitinib combined with buparlisib compared to ruxolitinib alone in patients with primary myelofibrosis
Patient population Patients with primary myelofibrosis from 18-65 years, who have an intermediate/high risk according to the DIPPS-score
Study design Part I) Dose finding study to find the optimal dose of ruxolitinib in combination with buparlisib.
Part II) A multicenter, cross-over clinical trial with randomization between ruxolitinib and ruxolitinib in combination with buparlisib
Duration of treatment Patients will be given a combination of ruxolitinib and buparlisib or ruxolitinib alone for 2 years
Number of patients Part I) 45 patients will be used to determine the maximum tolerated doses
Part II) 76 patients registered and randomized for induction treatment
Adverse events Adverse events will be documented if observed, mentioned or spontaneously reported
Planned start and end of 1-10-2015
5.1. Primary myelofibrosis
Together with polycythemia vera and essential trombocythemia, primary myelo-fibrosis (PMF) belongs to a group of haematological malignancies called myeloproliferative neoplasms (MPN). PMF is a chronic myeloproliferative neoplasm, characterized by fibrosis and chronic inflammation of the bone marrow. This is caused by uncontrolled growth of blood stem cells. The most common symptoms are:
‘ Tiredness, induced by anaemia
‘ Night sweats
‘ Weight loss
Furthermore, patients can experience loss of appetite, early satiety and a swollen abdomen, caused by splenomegaly, bone pain, increased sensibility for infection and gout. The chronic state of inflammation may result in extreme pruritus.
PMF is the least common of the MPNs with an incidence of 0,45 per 100.000 in Europe. The incidence in men is slightly higher than the incidence in women.1 PMF is more common at older ages. The mean age at diagnosis is 65 year and only 22% of the patients are under 56 years old. Criteria for diagnosis are defined in the WHO criteria (Addendum A).
The prognosis of PMF is extremely poor. Patients can be divided in 4 groups according to the DIPSS-plus (Addendum B) by the number of risk factors they have. These risk factors include age above 65 years, low haemoglobin level, high leukocyte count, over 1 % blasts in blood and constitutional symptoms. The DIPSS-plus classification adds transfusion dependency, low platelets and unfavourable cytogenetics to these risk factors. Patients in the low risk group have none of these risk factors. Patients with only one symptom have an intermediate-1 risk, 2 or 3 symptoms intermediate-2 and 4 to 6 symptoms have a high risk. The median survival for the low risk group is 185 months. The intermediate-1 group has a median survival of 78 months and for the intermediate-2 group this is 35 months. The median survival in the high risk group is only 16 months (fig. 1).2 Death is mainly caused by (acute) leukaemia, which occurs in 20% of the patients in 10 years. Other causes can be thrombosis, bleeding, infections, portal hypertension and secondary neoplasia.3
5.2. Current therapy
For patients with minimal symptoms, a wait-and-see policy is recommended. The only curative therapy is an allogeneic stem cell transplantation (SCT). This is only indicated for high risk and relatively younger patients, because of the high overall mortality of 20-40%. If an SCT cannot be performed, treatment is mainly symptomatic.
In cases of anaemia, low-dose prednisone or erythropoiesis-stimulating agents (ESAs) are used. ESAs have a response rate that varies from 20-60%. If ESAs are not indicated (in cases of transfusion dependency) or have lost their efficacy, danazol or androgen can be prescribed. Responses may occur after 3 months of treatment or beyond. As a last resort, low-dose thalidomide combined with prednisone can be used. This last treatment may have a lot of adverse effects and is often poorly tolerated, these adverse effects may include: peripheral neuropathies, constipation and somnolence.3
First line treatment of splenomegaly, the most common symptom of myelofibrosis, usually consists of hydroxyurea. 35% of the patients achieve over 25% reduction in spleen size. However, for this reduction higher doses are needed, which often have some serious adverse effects (for example cytopenias). For non-responders and patients with cytopenia, busulphan or melphalan may be an alternative. However, these are leukemogenic (only applicable in patients with a short life expectancy) and even more myelosuppressive and can induce severe cytopenias. Splenectomy may be performed if none of these drugs are effective or are not tolerated. In some cases, splenectomy has a positive effect on anaemia (50%) and thrombocytopenia (30%). Complications can be severe and examples are bleeding, thrombosis, infections, and a myeloproliferative reaction.3
Splenic irradiation can also be considered although the effect of this treatment holds only for median 9-11 months.
Thrombosis is treated pre-emptive in patients with risk factors. These include: age over 60 years, JAK2V617F mutations, high leukocyte count and a history of thrombosis. Patients receive hydroxyurea and low-dose aspirin.3
The only curative treatment, SCT, is only indicated for patients with a high mortality risk. First, a suitable donor has to be found. Ideally, stem cells will be taken from a direct family member. Unfortunately, a suitable family member is not always available, in these cases a donor will be searched in the database. Transplantations with non-family donors have a slightly worse prognosis. Preparation for the actual transplantation is tough and the risk of life-threatening complications during the procedure increases with age. The entire immune system of the patient will be eradicated and even the most innocent infection can result in enormous consequences like death. High-dose chemotherapy and irradiation may be required to eradicate the autologous bone marrow, a procedure that may induce serious side effects. Only after this eradication, the donor bone marrow can be administered.
Even after a successful transplantation, a high risk on severe complications is present. The most common adverse effect of an SCT is the graft-versus-host-disease (GVHD), which 40-60% of the patients develop. This chance is lower in patients who have bone marrow of a related donor, namely 30-40%. With all these effects taken into account, the overall mortality of the procedure itself is 20-40%. After 3 years, the overall survival of an ASCT is only 30-50%.
5.3. Pathogenetic mechanisms in Primary Myelofibrosis
As stated before, primary myelofibrosis is a myeloproliferative neoplasm. In this disease there is a proliferation of myeloid cells with various types of maturation and atypical megakaryocytic hyperplasia.4 The atypical megakaryocytes produce growth factors that cause secondary processes to occur. These growth factors include PDGF (platelet-derived growth factor), TGF-?? (transforming growth factor), bFGF (basic fibroblast growth factor), EGF (epidermal growth factor) and calmodulin.5
Bone marrow fibrosis and increased vascularity
The growth factors, produced by atypical megakaryocytes, stimulate fibroblastic proliferation and hyperactivity. Normal hematopoietic tissue is now replaced by collagen fibrosis, leading to a deficiency in normal blood cell formation. Other growth factors that are produced result in the formation of neovascularisations. These are factors like VEGF and PDGF.5
Extra medullary haematopoiesis
In primary myelofibrosis, haematopoiesis does not only occur in the bone marrow any more, but in other structures like the liver, the spleen, the skin and gastro-intestinal structures as well. The spleen is often enlarged because it tries to compensate for the loss of blood cells and because of an overload of myeloid cells, which it tries to eradicate.6 This enlargement contributes to pancytopenia, defined by thrombocytopenia, leukopenia and anaemia.
There are two mutations mainly involved in the pathogeneses of primary myelofibrosis: the calreticuline mutation and the JAK-2-mutation. Calreticuline (CALR) is a chaperone which regulates glycoprotein folding and plays a roll in calcium homeostasis in the endoplasmic reticulum. Furthermore calreticuline is present in the cytoplastic, cell surface and in extracellular compartments. Outside the endoplasmic reticulum it regulates apoptosis, proliferation, phagocytosis and immunogenic cell death. The JAK-2-mutation will further be described in chapter 5.3.1.
5.3.1. JAK2/PI3-AKT pathway
To understand the mechanisms of actions of both drugs used for our study, we will first explain a major pathway involved in the hematopoietic signalling. Hematopoietic signalling is mostly controlled by a group of tyrosine kinases receptors named Janus Kinases (JAKs). Proteins of the JAK family contain seven JAK homology domains (JH domains). Two well-known domains are the JH1 and the JH2 domain. JH1 consists partly of a kinase domain and is inhibited by the JH2 domain. There are four members of the family of these receptors, but to understand the drugs involved we will only discuss one of them. This receptor is the JAK2-receptor, which is activated by multiple ligands. Some of these ligands are EPO, IL-3, IL-5, GH and GM-CSF. After the ligand is bound to the receptor, the receptor gets phosphorylated. Signalling molecules like PI3K/AKT, mTOR and STAT can be activated by this pathway. This activation leads to proliferation and inhibition of apoptose.7
To understand the BKM-120, some explanation about the pI3K/AKT pathway is necessary. Not everything about this pathway has been understood yet. PI3K can produce phosphatidylinositol-3,4,5-trisphosphate (PIP3) by the phosphorylation of PIP2, which is bound in the membrane. PIP3 can activate protein kinase B (or AKT), which is a serine/threonine-specific protein kinase. This AKT can inhibit the apoptosis and is involved in cell cycle progression and cellular growth.8
In patients with primary myelofibrosis the JAK2-pathway is extremely important. Approximately 55% of the patients have a mutation in this pathway. Often, a V617F mutation in the JH2 domain is found, meaning that the JH1 domain is not inhibited anymore.7
5.4. Recently completed studies
Ruxolitinib is evaluated in various studies and is proven to be very effective in myelofibrosis. Spleen size was significantly reduced, quality of life did improve dramatically and the overall survival seems to be higher in patients treated with ruxolitinib compared with patients treated with the best available therapy. Two phase 3 trials have been performed: COMFORT I and COMFORT II. The first was a double blinded, randomized and placebo-controlled trial including patients with myelofibrosis who were resistant or unsuitable to the available therapies. After 24 weeks 41,9% had shown a decrease in spleen size of 35% or more. In a COMFORT-II, phase 3 study ruxolitinib was well tolerated in patients with myelofibrosis and also causes reduction of the splenomegaly. 28,5% of the patients showed spleen reduction of a minimum of 35% after 48 weeks, while patients in the best available therapy group, did not show any significant reduction of spleen size.9 Besides this primary endpoint at 48 weeks, secondary outcomes of these studies were reduction in splenomegaly at 24 weeks low toxicity, relieve of constitutional symptoms, weight gain and improvement of physical condition.10
Ruxolitinib is currently the only approved JAK2-inhibitor for myelofibrosis. Other inhibitors are investigated in on-going trials or had too many or severe adverse events. Up to now, there is no evidence that JAK2 inhibitors lower the allelic burden of JAK2V617F.11 However, not only patients with a JAK2 mutation responded to the therapy but also patients without this mutation showed improvement. This could mean that ruxolitinib influences not only mutated JAK2 but also wild-type JAK2.12 Furthermore, there is no proof of reversal of other disease features like reticular fibrosis.11
Nowadays, there is a study in progress in Birmingham and London. This study is called: ‘710 HARMONY: An open-Label, 2-Arm, Dose-Finding, Phase 1b Study of the Combination of Ruxolitinib and Buparlisib (BKM120) in Patients with Myelofibrosis (MF)’. BKM-120 is likely to lower the allelic burden of the JAK2-mutation and could have an influence on the reversal of bone marrow fibrosis in patients with myelofibrosis. The Harmony study examines the highest safe dose of both the medications by simultaneous administration. Also, this study is conducted to reveal the main side effects of both drugs.13 As a consequence, we will evaluate the toxic dose of ruxolitinib and BKM-120 combined and reveal the effect of the combination on the size of the spleen in comparison to ruxolitinib alone, with secondary outcomes like decrease in bone marrow fibrosis and transfusion dependency.
Mechanism of action
Ruxolitinib is a JAK1- and JAK2-inhibitor, which is short for Janus-associated kinase, which is a tyrosine-protein kinase. Inhibition of the pathway results in anti-proliferative and pro-apoptotic effects. It especially affects the wild-type JAK2-pathway and the mutated JAK2V617F less.
Two phase 3 COMFORT studies, as described before, have demonstrated that ruxolitinib reduces the enlargement of the spleen and improves symptoms and quality of life. Also, patients showed a reduction in cytokines and growth factors and besides that, an improvement in constitutional symptoms like itchiness, tiredness, abdominal discomfort, rapid saturation, night sweats and physical condition. Out of the transfusion dependent patients 14% became independent of the transfusion. Also, 60% had normalization of platelet levels after 3 months of using the drug.12 The elimination half-life of ruxolitinib is approximately three hours, which means that after three hours the quantity of the medicine in the plasma has been halved. The kidneys mainly carry out this elimination. The Tmax, the maximal plasma concentration, is reached after 1 hour.
Patients with intermediate or high-risk myelofibrosis have indications for treatment with ruxolitinib. This includes primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. The dose depends on the platelet count:
‘ Initial dose (platelet count >200 x 109 /L): 20 mg PO BID
‘ Initial dose (platelet count 100-200 x 109 /L): 15 mg PO BID
‘ Initial dose (platelet count 50 to <100 x 109 /L): 5 mg PO BID ' Titrate dose based on response; not to exceed 25 mg PO BID14 Side effects All side effects of ruxolitinib are dependent on the dose and reversible.12 Adverse effects of ruxolitinib include anaemia, thrombocytopenia, gastrointestinal disturbances, metabolic abnormalities, peripheral neuropathy and hyper acute relapse of symptoms during treatment discontinuation.15 5.5.2. BKM-120 Mechanism of action BKM-120, or buparlisib, is an inhibitor of the class I PIK3 in the PI3K/AKT kinase. The inhibitor enters the competition with ATP and thus makes sure the PI3K signalling pathway is not activated. This is done by the inhibition of the messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3). Buparlisib has been shown to be anti-proliferative, pro-apoptotic and anti-angiogenic in breast cancer and lung cancer.16 Effective dose An effective dose for BKM-120 has not clearly been discovered yet and there are still clinical trials going to determine an effective dose. However, one study has done a phase 1b study, in which they state that if a dosis of 15 mg ruxolitnib two times a day and 60 mg of buparlisib one time a day is combined, this seems to be effective.13 Side effects In studies done to evaluate BKM-120 in breast cancer, researchers figured that almost 50% of the patients developed mood alterations. These alterations disappeared two weeks after the medication was stopped or a SSRI was given.17 Also, effects like hyperglycaemia, rash, nausea and fatigue were described.18 These results may be related to the dose of the medicine, but additional pharmacokinetic information is necessary. 5.6 Rationale The average overall survival of PMF still is poor. With the arrival of the new drug ruxolitinib the quality of life of the patients has been significantly improved and also a survival benefit was obtained. However, it does not reduce the allelic burden of Jak2V617F. This means it cannot be used as curative therapy. SCT still is the only curative therapy and because of its high mortality rate, another curative therapy is required. A new development is a drug called buparlisib. Buparlisib inhibits one single part of the JAK2-pathway, namely the PI3k-pathway. Since this pathway if often mutated in patients with primary myelofibrosis, a response can be expected in these patients. This drug has already been proven to be anti-proliferative, pro-apoptotic and anti-angiogenic in preclinical cancer models and is thus likely to be an effective therapy. In our randomised phase I/II study, we intent to analyse the effects of buparlisib combined with ruxolitinib in patients with PMF. Since an optimal effective dosage for combining buparlisib and ruxolitinib has not been identified yet, we need to analyse this first. When an optimal effective dose has been found, we will measure the efficacy of the buparsilib/ruxolitinib combination and compare it to patients who will only receive ruxolitinib. The second part of the trial will be randomized and multicentre. Patients will be included in one of the two groups. These patients will receive the optimal effective dosage as found in part 1 of our trial 6. Study objectives The objectives of our phase I/II randomized study are: ' To establish an effective dose of buparlisib combined with ruxolitinib in patients with primary myelofibrosis ' To assess the efficacy of ruxolitinib combined with buparlisib compared to ruxolitinib alone in patients with primary myelofibrosis 7. Endpoints 7.1. Primary endpoints ' Percentage of patients that reach 35% reduction of spleen size in each group 7.2. Secondary endpoints ' Duration of maintenance of a > 35% reduction from Baseline in spleen volume among subjects in each arm
‘ Percentage of patients that reach a 1 grade reduction of fibrosis in their bone marrow in each arm.
‘ Percentage of patients that have become transfusion dependent or transfusion independent in each arm
‘ Percentage of patients that reach a reduction of the allelic burden of JAK2V617F in each arm
‘ Percentage of patients that reach a reduction in atypical megakaryocytes in each arm
‘ Change in total symptom score from Baseline as measured by the MFSAF questionnaire
‘ Overall survival
8. Study design
8.1. Part I versus part II
8..1.1. Part I: Dose selection
Although doses up to 25 mg a day have been administered to patients with primary myelofibrosis and found to be feasible, it is unknown whether the combination of ruxolitinib and buparlisib will lead to other or earlier occurring toxicities. For this reason, the drug will now need to be taken to the relevant setting of treatment of newly diagnosed untreated patients. Decisions regarding feasibility and dose escalation to the next cohort, continuation or stopping are based on the incidence of DLT (Dose Limiting Toxicity), and will be performed according to the decision rules, described below. The Common Terminology Criteria for Adverse Events (CTCAE), version 4.02, 15sep09 will be used to grade toxicities.
Incidences of DLTs in patients treated in both groups will be compared. DLTs are defined as followed:
– Any non-haematological toxicity CTCAE ‘ grade 4
DLT will be used in the decision proves for dose escalation, dose reduction and/or dose selection.
The decision rules for ending the protocol treatment are:
– Receiving six weeks of treatment without a DLT
– Has experienced DLT.
8.1.2. Part II: Efficacy
Following the final dose selection a total number of 76 patients will be randomized to receive a selected dose of ruxolitinib (dependent on the platelet count) or the selected dose ruxolitinib/buparlisib. For details, see chapter 17.
8.2. Treatment design
8.2.1. Part I: Dose selection
45 patients will be used to determine a Maximum Tolerated Dose (MTD). We divided the patients in three different groups, based on their platelet counts. At first, three patients of each group will be given the lowest dose of buparlisib for six weeks as explained in chapter 9. If no DLTs show up, three new patients will be given a higher dose of buparsilib. This will continue until a DLT shows up to a maximum dose of buparlisib of 80 mg a day.
If a DLT occurs, the patient will be treated with a 10mg lower dose of buparlisib in the combination therapy, until a tolerable dose is reached. He or she will be replaced by two new patients, who will receive the dose at which the previous patient had a DLT. The study will proceed with these new patients and with the patients who are still in the group. If one or two DLTs show up in one group, the study may proceed to a higher dose level. There is a maximum on the amount of DLTs that may occur, namely three DLTs per platelet count group. If three DLTs occur, the dose will be adjusted to an intermediate dose between the toxic dose and the highest tolerable dose. This dose will also be tested on three new patients. Eventually, the maximum tolerated dose will be determined in each platelet count group.
8.2.2. Part II: Efficacy
Patients in this part of the study will be randomly divided into two groups. The control group will receive the already approved drug ruxolitinib. The other group will receive a combination of ruxolitinib and buparlisib. This group is set up to compare the efficacy of the addition of another specific JAK2-inhibitor to ruxolitinib. For details about the randomisation, see chapter 15. In this part of the study, 76 patients will be included (as shown in chapter 17), which means 75 patients per group. The study will continue for two years.
After six months an evaluation of patients will take place to see if there is a clinical response. A clinical response is defined as a reduction of the spleen in comparison to the spleen size at baseline. When a clinical response is evaluated, the patients will continue taking the drugs in the group they were assigned to until the end of the study, unless one of the events described in chapter 10 occurs. If there is no clinical response noticed at all, the patients will be assigned to the other group in the study, as can be seen in the study scheme (chapter 1). After another six months (one year after the beginning of the study), a second evaluation will be performed. Again, the clinical response will be evaluated. When there is still no response shown, this will be a valid reason to end the protocol treatment for the particular patient. After one year, the patients who received ruxolitinib only and had a CR, will receive the combination therapy to evaluate whether a deeper response can be reached.
After two years the study will be ended with the remaining patients in the groups. All patients will be analysed according to an intention-to-treat analysis, as explained in chapter 17.
9. Study population
9.1. Inclusion criteria
‘ Age 18-70 years old
‘ Patients must be diagnosed with primary myelofibrosis according to the WHO-criteria (addendum A)
‘ Patients must have an intermediate 1 or 2 or high risk according to the DIPSS plus score (addendum B)
‘ Patients must have an enlarged spleen which has to be palpable at least 5 cm below the costal margin
‘ Acceptable laboratory assessments within 14 days prior to first dose, including creatinin, urea, sodium, potassium, uric acid, calcium, glucose, bilirubin, AST, ALT, alkaline phosphatase, gamma GT and LD
‘ Patients with a performance status of 0, 1 or 2 according to the WHO criteria (addendum C)
‘ Patients who are willing to use contraception during and a few months after the trial to prevent pregnancy
‘ Platelet count > 50*109 /L
‘ Informed consent
9.2. Exclusion criteria
‘ Patients eligible for allogeneic stem cell transplantation
‘ Patients with a life expectancy of less than 6 months
‘ Patients previously treated for primary myelofibrosis
‘ Women who are pregnant or are breastfeeding in time of the study
‘ Current severe or uncontrolled medical condition
– Diabetes etc.
– Uncontrolled hypertension
‘ Clinically significant infection
– HIV-positive patients
– Hepatitis A, B or C
‘ Cardiac dysfunction
– Patients who have had a myocardial infection in the previous 6 months
– Unstable angina pectoris
– Unstable cardiac arrhythmias
– Prolonged QTc > 450 ms
‘ Patients who have had radiotherapy to their spleen or prior splenectomy
‘ Patients who have liver or kidney diseases
‘ Use of strong CYP3A4 inhibitors or strong CYP3A4 inducers within one week prior to first dose of IP.
‘ Patients who have had mental health issues in the past
‘ Patients who have problems with an alcohol or drug addiction that could affect the patient taking part in the study
‘ Prior use of JAK2 inhibitors
‘ Peripheral neuropathy greater or equal to CTCAE grade 2
10.1. Dose level of the combination of ruxolitinib and buparlisib
10.1.1. Part I: Dose selection
In part I of the study, we will divide our patients in three groups, based on their platelet count. As illustrated in the table below, the different doses of ruxolitinib have already been determined. Each group will start with a dose level of buparlisib of 20mg a day. If possible, according to the decision rules described in chapter 7, buparlisib will be elevated. Doses will be elevated with steps of 20 mg up till a maximum of 80 mg a day. The second dose will thus be set at a level of 40 mg a day. If a patient does not tolerate a dose, his or her dose will be lowered with 10 mg a day. If this intermediate dose is not feasible, we will return to the tolerable dose. However, if our start dose of 20 mg a day is not feasible, the trial will be closed.
Platelet count: 50-100
Platelet count: 100-200
Platelet count: <200 First dose BKM-120 20 mg BID ruxolitinib + 20 mg QD buparlisib 15 mg BID ruxolitinib + 20 mg QD buparlisib 5 mg BID ruxolitinib + 20 mg QD buparlisib Second dose BKM-120 20 mg BID ruxolitinib + 40 mg QD buparlisib 15 mg BID ruxolitinib + 40 mg QD buparlisib 5 mg BID ruxolitinib + 40 mg QD buparlisib Third dose BKM-120 20 mg BID ruxolitinib + 60 mg QD buparlisib 15 mg BID ruxolitinib + 60 mg QD buparlisib 5 mg BID ruxolitinib + 60 mg QD buparlisib Fourth dose BKM-120 20 mg BID ruxolitinib + 80 mg QD buparlisib 15 mg BID ruxolitinib + 80 mg QD buparlisib 5 mg BID ruxolitinib + 80 mg QD buparlisib 10.1.2. Part II: Efficacy The dose of the combination of buparlisib and ruxolitinib for part II will be selected in part I and will still be depended on the platelet count. 11. End of protocol treatment Reasons for going off protocol treatment are: ' Normal completion of the protocol ' No response on treatment ' Severe adverse events ' Excessive toxicity ' Intercurrent death, whatever the cause ' No compliance of the patient ' Major protocol violation 12. Required clinical evaluations 12.1. Time of clinical evaluations ' At entry baseline, at least 4 weeks before start protocol ' Every 8 weeks clinical evaluation and response assessment 12.2. Required investigations 12.2.1. Informed consent / eligibility criteria ' If the patient fits the eligibility criteria, he or she has to sign an informed consent at the beginning of the trial, to ensure that the patient fully understands the consequences of joining the study and agrees to the terms. 12.2.2. Medical history ' Standard medical history, including: - Prior and present other diseases - WHO performance status - Toxicities - Infections ' Only at entry - Antecedent haematological or oncological diseases - Previous chemotherapy, radiotherapy and other oncological therapies - Siblings 12.2.3. Prior and concomitant medication ' At the beginning and during the trial ask if there is any use of medication that could interfere with one of the endpoints of the study 12.2.4. Transfusion history / status ' Check every visit if the patient depends on blood transfusions and what the status is of this dependence 12.2.5. Physical examination ' Standard examination of the body weight and height. Special attention is needed for spleen size, infections and toxicities 12.2.6. Vital signs ' Blood pressure ' Heart rate ' Respiratory rate ' Body temperature 12.2.7. Pregnancy test ' Pregnancy could cause bias in the results. Also, the medication could have a negative effect on the development of the foetus. A pregnancy test is conducted every six months to avoid these events to occur 12.2.8. MF-SAF ' The Myelofibrosis Symptom Assessment Form (MF-SAF) will be used to determine the quality of life. The MF-SAF consists of questions about symptoms matching myelofibrosis and about the influence of myelofibrosis on the normal daily activities (addendum D) 12.2.9. Hematology ' A complete hemogram is used to check if there are any important developments in the blood status. Special attention for: - Erythrocytes - Leukocytes - Platelet count - Haemoglobin - Leukocytes differential count, including description of circulating erythroblasts and reticulocytes - Recovery of peripheral blood cells. 12.2.10. INR and PTT ' The protrombin time and partial thromboplastin time have to be checked alongside the hemogram. The INR and PTT provide an image of the risk of bleedings and thrombosis. 12.2.11. Complete Screening Symptom Form ' The Complete Screening Symptom Form is used to determine the severity of the symptoms in the past seven days (addendum E). 12.2.12. ECG ' An ECG is performed to discover whether or not co-morbidity is a cause of mortality or complications during the study. The QTC time will have to be determined, because a QTC time >450 ms is an exclusion criteria. Also, the medication could have an influence on the cardiac status
12.2.13. Serum chemistry test
‘ The serum chemistry test can give information about variations caused by the medication. Every visit the following factors are tested:
– – Albumin
– Alkaline phosphatase
– ALT AST
– Gamma glutamyl transferase
– Lactate dehydrogenase
– Serum lipase
– Total bilirubin
– Total protein.
12.2.14. Molecular analysis
‘ To evaluate the amount of patients with a JAK2-mutation. This JAK2-mutation has to be determined in the blood plasma, which is done before randomization and at 6, 12, 18 and 24 months. We will perform a quantitative analysis of the allelic JAK2 burden at the same time points.
12.2.15. Plasma level of BKM-120
‘ To determine the kinetics and metabolism of the medicine, the plasma level of this medicine has to be determined every control.
12.2.16. Lipid panel
‘ Because there could be some side effects that may influence the lipid panel, this has to be determined every control. Factors that will be determined are:
– – Total cholesterol
12.2.17. Bone marrow aspiration and biopsy
‘ Bone marrow aspiration and biopsy must be done every 6 months and has to be evaluated by a pathologist. When fibrosis is shown, this must be graded using the European consensus grading (addendum F). Also, in this addendum is explained how the bone marrow aspiration should be evaluated.
12.2.18. Spleen size
‘ To determine the size of the spleen, a doctor must palpate the spleen every 8 weeks. Furthermore, a MRI has to be done every 6 months.
12.2.19. Record adverse events
‘ To make sure adverse events in the study do not go unnoticed, the patients must be asked every visit if he or she is experiencing such events.
The toxicities of the combination of these drugs have already been evaluated in another study and are added in addendum G. However, we will still evaluate these outcomes in our own study. The toxicities will be evaluated according to a questionnaire called the ‘Common Terminology Criteria for Adverse Events (CTCAE)’, version 4.02, 15sep09 (addendum H).
14. Reporting serious adverse events and SUSARS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical study subject during protocol treatment. An AE does not necessarily have a causal relationship with the treatment. It can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product (IP), whether or not related to the medicinal (investigational) product.
Adverse reactions (AR) are those AEs of which a reasonable causal relationship to any dose administered of the investigational medicinal product and the event is suspected.
A Serious adverse event (SAE) is defined as any untoward medical occurrence whether or not considered related to the therapy that at any dose results in:
‘ a life-threatening event (i.e. the patient was at immediate risk of death at the time the reaction was observed)
‘ hospitalization or prolongation of hospitalization
‘ significant / persistent disability
‘ a congenital anomaly / birth defect
‘ any other medically important condition (i.e. important adverse reactions that are not immediately life threatening or do not result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed above)
Note that any death, whether due to side effects of the treatment or due to progressive disease or due to other causes is considered as a serious adverse event.
Unexpected Serious Adverse Events are those SAE’s of which the nature or severity is not consistent with information in the relevant source documents. For a medicinal product not yet approved for marketing, the Investigator’s Brochure will serve as a source document.
Suspected unexpected serious adverse reactions (SUSARS) are suspected ARs which occur in the trial and are both unexpected and serious.
14.2. Reporting of serious adverse events
During protocol treatment all deaths, all SAEs that are life-threatening and any unexpected SAE must be reported to the HOVON Data Center by fax within 48 hours of the initial observation of the event, except hospitalizations for:
‘ A standard procedure for protocol therapy administration. Hospitalization or prolonged hospitalization for a complication of therapy administration will be reported as a Serious Adverse Event.
‘ The administration of blood or platelet transfusion. Hospitalization or prolonged hospitalization for a complication of such transfusion remains a reportable serious adverse event.
‘ A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, sampling for laboratory tests, bone marrow sampling). Hospitalization or prolonged hospitalization for a complication of such procedures remains a reportable serious adverse event.
‘ Prolonged hospitalization for technical, practical, or social reasons, in absence of an adverse event.
‘ A procedure that is planned (i.e., planned prior to starting of treatment on study; must be documented in the source document and the CRF). Prolonged hospitalization for a complication considered to be at least possibly related to the study drug remains a reportable serious adverse event.
All details should be documented on the Serious Adverse Event and Death Report. In circumstances where it is not possible to submit a complete report an initial report may be made giving only the mandatory information. Initial reports must be followed-up by a complete report within a further 14 calendar days and sent to the HOVON Data Center. All SAE Reports must be dated and signed by the responsible investigator or one of his/her authorized staff members.
The investigator will decide whether the serious adverse event is related to the treatment (i.e. unrelated, unlikely, possible, probable, definitely and not assessable) and this decision will be recorded on the serious adverse event form. The assessment of causality is made by the investigator using the following:
14.3. Processing of serious adverse events
The Data Center will forward all reports within 24 hours of receipt to the principal investigator and the study central data manager. The report of an SAE will be the signal for the central data manager to ask the investigator or the responsible local data manager to send all relevant CRFs for the involved patient with details of treatment and outcome as soon as possible. It is of utmost importance that all SAEs (including all deaths due to any cause) are reported in a timely fashion. Patients without a report of an SAE are implicitly considered alive without SAE. This information will be used in monitoring the incidence of SAEs, the estimation of overall survival and monitoring of safety of experimental treatments.
Any suspected unexpected serious adverse reactions (SUSARs) arising from this trial will be reported expedited by HOVON to the investigators and to all applicable Ethics Committees and Health Authorities within the timelines required by the EU Clinical Trial Directive. The manner of SUSAR reporting will be in compliance with the procedures of the Ethics Committees and Health Authorities involved.
Patients should be registered immediately after confirming joining the study. A few data must be provided to the HOVON Data Center.
15.1. Regulatory documentation
‘ Ethics Committee approval, including a name, address and list of the current members
‘ Informed consent form for the investigational site
‘ Informed consent form and Patient Information for the patient
‘ CV investigator
‘ Signed local investigator signature page of the protocol
15.2. Registration and randomisation
‘ Protocol number
‘ Institution name
‘ Name of caller/responsible investigator
‘ A copy of informed consent
‘ Patient’s initials or code
‘ Patient’s hospital record number
‘ Date of birth
‘ Date of diagnosis
‘ WHO performance status
‘ In- and exclusion criteria (eligibility criteria)
All data will be checked according to a checklist. Each patient will be given a personal unique patient study number. Patient study number will be given immediately by TOP (Trial Online Process, https://www.hdc.hovon.nl/top) or phone and confirmed by fax or email.
16. Data collection
Data will be collected on Case Report Forms (CRF) to document eligibility, safety and efficacy parameters, compliance to treatment schedules and parameters necessary to evaluate the study endpoints. We built the CRF in Castor EDC. Data collected on the CRF are derived from the protocol and will include at least:
‘ Inclusion and exclusion criteria
‘ Baseline status of patient including medical history and stage of disease
‘ Timing and dosage of protocol treatment
‘ Adverse events
‘ Parameters for response evaluation
‘ Any other parameters necessary to evaluate the study endpoints
‘ Survival status of patient
‘ Reason for end of protocol treatment
Each CRF page will be identified by a pre-printed trial number and a unique combination of patient study number (assigned at registration), hospital and patient namecode (as documented at registration) to be filled out before completing the form.
The CRF will be completed on site by the local investigator or an authorised staff member. Each page must be dated and signed by the local investigator upon completion. All CRF entries must be based on source documents. The CRF and written instructions for completing the CRF are added as addendum I.
Copies of the CRF will be kept on site. The original CRF pages must be sent to the HOVON Data Center at the requested time points. How and when to send in forms is described in detail in the CRF header and the CRF instructions.
All data from the CRF will be entered into the study database by the HOVON Data Center.
17. Statistical considerations
17.1. Phase I: Dose finding study
In our phase I study we will use the 3×3 design. This means that the study starts with three patients in the group with a platelet count of more than 200 x 109 / L, three patients in the group with a platelet count between 200 and 100 x 109 / L and three patients in the group with a platelet count between 100 and 50 x 109 / L. These patients will all start with the lowest dose of 20 mg qd buparlisib.
If there are no dose-limiting toxicities (DLTs) in these groups within six weeks, the next nine patients will start with a dose of 40 mg qd buparlisib. This adding of the dose will go on until 80 mg qd buparlisib is reached or until a DLT occurs within a patient. If a DLT occurs, this patient will be replaced by one of two other patients. In case no more DLTs occur, the study will continue to the next dose level.
A DLT is defined as: ‘Death or any non-haematological toxicity CTCAE grade ‘ 4’. Overall, we need 36 patients for our phase I study. To take in account the loss of patients due to the DLTs, we determined a total of 45 patients. When three or more DLTs occur in one platelet count group, we will not include any other patients in the next dose level. This dose will then be considered as the maximum tolerated dose (MTD).
17.2. Phase II: Efficacy study
17.2.1. Patient numbers and power considerations
In our phase II study we estimated the power with the formula in figure 3. In previous studies with ruxolitinib therapy a more than 35% reduction of spleen size was found in 28,5% of the patients. We assume that our therapy will have a higher response rate, so we determined a response rate of 50%. Furthermore, we used:
‘ ?? = 0,05
‘ ?? = 0,20
‘ Power (1 ‘ ??) = 0,80
‘ Z?? = 1,65
‘ Z?? = 0,84
With these factors we can establish the patient sample size, using the formula in figure 3. In our case we established a patient sample size of 71,3 patients in each arm. We suspect a patient loss of 5% during our study. Therefore the patient sample size is adjusted to 74,865 patients in each arm. Not all of the patients who register at the trial measure up to the inclusion criteria, so assumed that 66% measures up to our criteria, we need 227 patients to register at our trial. We randomize the 150 (or more) patients into two arms. This means that at least 75 patients will be included in each arm.
17.2.2. Statistical analysis
All main analysis will be analysed according to the intention to treat analysis. This means that we will analyse all the randomized patients, according to the medication they were supposed to take. However, patients who at first were randomized but due to information that should be available before randomisation, do not measure up to the inclusion criteria, are excluded from the analysis.
184.108.40.206. Efficacy analysis
Our primary endpoint is the number of patients who have more than 35% reduction of spleen size. We will measure this every eight weeks by palpation and every six months by using the MRI-scan. After two years we will determine the number of patients with more than 35% reduction of spleen size in the different arms. We will further analyse this by using an incidence rate ratio, which is the ratio of the incidence rate in the ruxolitinib group and the incidence rate in the ruxolitinib ‘ buparsilib combination group. The incidence we will use is the number of patients who have more than 35% reduction of spleen size.
Furthermore, we can extend this with one of the secondary endpoints, the maintenance of the spleen reduction. Other secondary endpoints, as described in chapter 14.2, can also be analysed with an incidence rate ratio. The overall survival will be analysed with the Kaplan ‘ Meier method.
220.127.116.11. Toxicity analysis
The treatment toxicities are listed according to the Common Terminology Criteria for Adverse Events (CTCAE) (addendum G). All the adverse events, of both the ruxolitinib and ruxolitinib ‘ buparsilib combination group, with a CTCAE grade of 2 or higher are registered. These adverse events are also used in the safety analysis.
18.104.22.168. Additional analysis
The secondary endpoints can also be used to determine prognostic factors for the level of reduction in spleen size, for example the amount of JAK2 allelic burden, the amount of fibrosis in bone marrow and the quality of life. This can be analysed by using a logistic or Cox regression model.
Furthermore, we also determine the impact of the platelet count on the disease burden. The difference in level of spleen reduction between the several platelet count groups will be used to do that.
17.2.3. Interim analysis and safety monitoring
We planned three interim analyses during our research. These take place every six months after the required investigations (chapter 11). After each of these interim analyses, the information will be given to an independent data and safety monitoring board (DSMB). The information includes patient sample size, patients treated at the moment of the analysis, given treatment and incidence of serious adverse events, events and infections. The (serious) adverse events and infections are listed by number, CTCAE grade and relation to treatment given.
The DSMB will determine on the basis of this information if the study may continue or has to stop. Also once a year, we will send a special report of all the serious adverse events and infections. The DSMB is free in her public recommendations to the principal investigators and her confidential recommendation to the trial statistician.
18. Trial insurance
The HOVON insurance program covers all patients from participating centers in the Netherlands according to Dutch law (WMO). The WMO insurance statement can be viewed on the HOVON Web site http://www.hovon.nl.
Individual participating centers from outside the Netherlands have to inform the HOVON about the national laws regarding the risk insurance of patients participating in a study. If necessary, HOVON will extend the insurance to cover these patients.
19. Publication policy
The final publication of the trial results will be written by the study coordinator(s) on the basis of the statistical analysis performed at the HOVON Data Center. A draft manuscript will be submitted to the Data Center, all co-authors and the sponsor for review. After revision by the Data Center, the other co-authors and the sponsor, the manuscript will be sent to a peer reviewed scientific journal.
Authors of the manuscript will include the study coordinator(s), the lead investigators of the major groups (in case of intergroup studies), investigators who have included more than 5% of the evaluable patients in the trial (by order of number of patients included), the statistician(s) and the HOVON data manager in charge of the trial, and others who have made significant scientific contributions.
Any publication, abstract or presentation based on patients included in this study must be approved by the study coordinator(s). This is applicable to any individual patient registered/randomized in the trial, or any subgroup of the trial patients. Such a publication cannot include any comparisons between randomized treatment arms nor an analysis of any of the study end-points unless the final results of the trial have already been published.
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