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Novel dual HDAC/PI3K inhibitor assessed in lymphoma, myeloma
An oral, first-in-class, small molecule inhibitor (CUDC-907) designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, has demonstrated promising preliminary evidence of response in patients with diffuse large B-cell lymphoma, a new study published in The Lancet Oncology has shown.
Because treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited, researchers developed CUDC-907, which inhibits enzymes that are members of common oncogenic pathways in hematologic malignancies.
In this US multicentre, open-label, phase 1 dose-escalation study, researchers assessed the overall safety and preliminary activity of CUDC-907 monotherapy in this patient population.
The trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres.
CUDC-907 was orally administered in a standard three plus three dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: Once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for five days followed by a two-day break (five/two), in 21-day cycles. Dosing started at 30mg for the once-daily schedule and 60mg for other schedules, escalating in 30mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met.
The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66 per cent of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. The researchers assessed safety in all patients who received at least one dose of study drug.
Between 23 January 2013, and 27 July 2015, the trial enrolled 44 patients, of whom 10 were sequentially assigned to CUDC-907 once-daily (MTD 60mg), 12 to twice-weekly (MTD 150mg), 15 to three-times-weekly (MTD 150mg), and seven to the five/two dosing schedule (MTD 60mg).
Eighty-four per cent (37) of patients had discontinued the study drug as a result of progressive disease or clinical signs of progressive disease at the data cut-off.
Four DLTs occurred in three-of-40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60mg once-daily, hyperglycaemia in one patient on 150mg twice-weekly, and diarrhoea in one patient on 150mg three-times-weekly); no DLTs were reported in patients on the five/two schedule.
Grade 3 or worse adverse events occurred in 19 (43 per cent) of 44 patients, the most common of which were thrombocytopaenia (in nine [20 per cent] of 44 patients), neutropaenia (three [seven per cent]), and hyperglycaemia (three [seven per cent]). Eleven (25 per cent) of 44 patients had serious adverse events, three of which were regarded as treatment-related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14 per cent) patients and treatment discontinuation in seven (16 per cent).
In terms of efficacy, five (14 per cent) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). Twenty-one (57 per cent) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin’s lymphoma, and multiple myeloma.
On the basis of these findings, the researchers selected CUDC-907 60mg on the five/two dosing schedule as the recommended phase 2 dose.
The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60mg five/two dosing schedule, alone and in combination with other therapies, the researchers concluded. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing.
Analysis of outcomes of haemophilia care over 50 years is published
In spite of advances in haemophilia therapies over the last half century, men with severe forms of this disease still experience physical limitations and disability, according to new research published in Blood, the journal of the American Society of Haematology (ASH).
The research also reveals that the incidence of joint bleeding also remains higher than expected, even among a subset of men with mild haemophilia.
“Our analysis provides a snapshot of how improvements in care have translated into outcomes across different generations of men with haemophilia,” said Dr Paul E Monahan, of the Gene Therapy Centre at the University of North Carolina, US, and one of the study’s authors.
“While there is reason to be pleased with the progress we have made, our data show some surprising deficits and suggest that efforts are needed to more consistently apply the integration of standard of care multidisciplinary services and preventive blood clotting factor treatments to further normalise the lives of men living with haemophilia.”
Because the disease is inherited through a defect in the X chromosome, it is more common in males than females.
Dr Monahan and his team analysed data for 7,486 men with haemophilia collected prospectively by the CDC and 130 federally supported haemophilia treatment centres (HTC) between 1998 and 2011, which represents the largest database of men living with haemophilia.
They grouped the men into four birth cohorts to evaluate how outcomes – access to care, physical and social functioning, complications, and mortality – have changed over the last 50 years.
Researchers further analysed the data to compare the experience of 4,899 men with severe haemophilia with those of 2,587 men living with mild haemophilia to control for outcomes like ageing or environment that would be expected to similarly impact all men within each birth cohort, independent of the severity of the clotting deficiency.
Based on their analysis, researchers discovered that men with severe haemophilia were three times as likely to report limitations in their activities or be disabled, compared to those with mild haemophilia, regardless of when they were born. These men were also more likely to report missing 10 days of work or school during the previous year.
Frequent bleeding was common even among men with severe haemophilia in the youngest birth cohort – despite access to effective, safe clotting therapies and multidisciplinary care having been available throughout the lifetime of men in this era. In this group of men with severe haemophilia, one-in-three report having more than five bleeding events in six months, and one-in-four has a joint affected by recurrent bleeding.
“Clear disparities remain in terms of frequent bleeding and disability between men with severe haemophilia and mild haemophilia across every decade of adult life,” said Dr Monahan. “We thought the difference in functional outcomes would have narrowed over the years; that is, men with severe haemophilia should look more like those with mild disorder given improved therapeutics and access to care, but this was not the case.”
Study points towards prevention strategies for blood cancers
New research has shown the potential to prevent blood cancer from developing by reducing the level of the MCL-1 protein in the body.
The research follows on from a discovery announced in 2014 that showed that a cancer-causing protein (MYC) could be reduced by disabling the MCL-1 protein.
MYC is found in abnormally high numbers in approximately 70 per cent of cancers.
The research was conducted by the Walter and Eliza Hall Institute of Medical Research in Australia.
“No one had realised just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” according to one of the research leaders, Dr Stephanie Grabow.
“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anti-cancer drugs.”
“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers. We have now shown that the same approach might be able to prevent those cancers from forming in the first place,” Dr Grabow said.
“Prevention is the holy grail in the context of cancer. Put simply, if we can stop the cancer from developing, thousands of families each year could be spared from immeasurable pain and heartache.
Recommended dosing for leukaemia therapy identified
The once-daily recommended dose for oral, single agent OTX015 use in patients with acute leukaemia for further phase 2 studies is 80mg on a 14 days on, seven days off schedule, according to the results of a recent clinical trial recently published in The Lancet.
Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription. OTX015 inhibits proliferation in many haematological malignancy cell lines and patient cells, in vitro and in vivo.
The researchers aimed to establish the recommended dose of OTX015 in patients with haematological malignancies and the reported results are for patients with acute leukaemia.
In this dose-escalation, phase 1 study the researchers recruited patients from seven university hospital centres (France [five], UK [one], and Canada [one]).
Adults with acute leukaemia who had failed or had a contraindication to standard therapies were eligible to participate.
OTX015 was given orally at increasing doses from 10mg/day to 160mg/day (14 of 21 days), using a conventional three plus three design.
In this open-label trial, OTX015 was initially administered once a day, with allowance for exploration of other schedules. The primary endpoint was dose-limiting toxicity (DLT), assessed during the first treatment cycle (21 days).
Forty-one patients, 36 with acute myeloid leukaemia, a median age of 70 years (IQR 60–75), and two lines of previous therapy, were recruited and treated across six dose levels of OTX015. No DLT was recorded until 160mg/day, when one patient had grade 3 diarrhoea and another had grade 3 fatigue. However, concomitant grade 1-2 non-DLT toxic effects (ie, gastrointestinal, fatigue, or cutaneous) from 120mg doses hampered patient compliance and 80mg once-a-day was judged the recommended dose with a 14 days on, seven days off schedule. Common toxic effects for all OTX015 doses were fatigue (including grade 3 in three patients) and bilirubin concentration increases (including grade 3-4 in two patients).
OTX015 plasma exposure increased proportionally up to 120mg/day with trough concentrations in the in vitro active range from 80mg/day (274nmol/L).
Three patients (receiving 40mg/day, 80mg/day, and 160mg/day) achieved complete remission or complete remission with incomplete recovery of platelets lasting two and five months, and two additional patients had partial blast clearance. No predictive biomarkers for response have been identified so far.
The study is ongoing.