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New Agent Shows Synergy With JAK Inhibitor in Myelofibrosis After Ruxolitinib Failure

Danielle Ternyila
Published Online:12:35 PM, Thu June 27, 2019
Marina Kremyanskaya, MD, PhD
Marina Kremyanskaya, MD, PhD
Bromodomain and extra-terminal protein (BET) inhibitor CPI-0610 has demonstrated activity in preclinical trials for myelofibrosis (MF) and received a fast track designation from the FDA in November 2018. Data also showed that the combination of ruxolitinib (Jakafi) plus CPI-0610 has had a synergistic effect and was able to reduce MF-related toxicities such as splenomegaly and bone marrow fibrosis.

In a phase II clinical trial, 18 patients with MF who had previously progressed on ruxolitinib, were not receiving an adequate response on ruxolitinib, or had never received a JAK inhibitor before and were dealing with MF-related anemia, were enrolled and given either CPI-0610 as a monotherapy or in combination with the JAK2 inhibitor. Investigators aimed to evaluate the effect of CPI-0610 on transfusion dependence, spleen volume, as well its effect on MF-related toxicities.

Two patients in the combination arm became transfusion dependent and remained free of transfusions. In addition, there was a hemoglobin increase in patients with anemia in 100% of patients in the combination arm and 33% in the monotherapy arm. Spleen volume was reduced and observed by MRI in 14 of 16 evaluable patients irrespective of their mutation driver. 

Investigators also observed an improvement in symptoms and reductions in cytokine levels; 100% of patients in the monotherapy arm had improvement in bone marrow fibrosis with an increase in hemoglobin. The most common adverse events (AEs) included mild diarrhea, nausea, vomiting, and reversible and non-cumulative thrombocytopenia.

In an interview with Targeted Oncology, Marina Kremyanskaya, MD, PhD, a hematologist-oncologist at Mount Sinai Hospital, discussed the results from the phase II trial investigating the effects of CPI-0610 with or without ruxolitinib in patients with MF. Overall, the drug was well tolerated and effective in patients who had previously progressed on ruxolitinib or received inadequate responses to treatment.

TARGETED ONCOLOGY: What was the rationale for investigating CPI-0610 in patients with MF?

KremyanskayaMF is a chronic myeloid malignancy, and currently there’s only 1 medication that’s approved: ruxolitinib. For patients that don’t tolerate [ruxolitinib] or have to come off of it for whatever reason, there’s limited treatment options that are left. That leaves the experimental treatments as their best options. Also, it’s been documented that patients who come off ruxolitinib, the typical average survival is around 14 months, so we need improved treatment options for these patients.

This study is a phase II of this CPI-0610, which is a BET inhibitor; it’s a new type of epigenetic therapy, and it’s been studied as either monotherapy for patients who have been treated with ruxolitinib previously and didn’t tolerate it or progressed on it then came off of it prior to starting this trial, or for patients who are on ruxolitinib but are not getting an optimal response on it. The patient population that’s being presented in this poster is these 2 cohorts of patients, and [they received] either monotherapy or were in the combination arm.

TARGETED ONCOLOGY: How was this trial designed?

KremyanskayaThese 2 cohorts of patients are started on this therapy, and we are looking for the typical responses that we have in patients with MF. Patients with MF tend to have anemia; 1 of the major factors of these patients is splenomegaly, and 1 of the big parameters that we look at in clinical trials is improvement in splenomegaly. The other parameters are improvement in bone marrow fibrosis as a marker of the disease process itself and other blood counts like thrombocytopenia and things like that. Another important factor is improvement in symptoms; we were looking at all of these parameters in these patients, and right now these are preliminary data. We don’t have enough patients yet that have been treated long enough to be evaluable for these endpoints. We are looking at patients who have been on treatment for at least 6 months.

TARGETED ONCOLOGY: What exactly makes the agent CPI-0610 so unique compared to other drugs in MF?

KremyanskayaThis is a medication that is active at the epigenetic level, so it’s different from the JAK inhibitors that have seen a lot in MF. What’s interesting is that the downstream effect should be effective in the NF-κB pathway. There’s some preclinical data looking at mouse models with MF that showed that the combination of a JAK inhibitor such as ruxolitinib and a BET inhibitor tend to have a synergistic effect in terms of improvement of splenomegaly, bone marrow fibrosis, and improvement in anemia. We are hoping to see the same kind of affect with the combination of these drugs in patients as well.

TARGETED ONCOLOGY: What were the findings from this trial with CPI-0610 in MF?

KremyanskayaWhat we are seeing right now is that this medication either as monotherapy or in combination is actually very well tolerated. One of the major [adverse] effects that we worry about specifically with a BET inhibitor is thrombocytopenia, and it’s doubly concerning because ruxolitinib also causes thrombocytopenia. We were concerned that we would see extensive thrombocytopenia, especially in the combination arm. That did not happen, so patients tolerated the therapy very well. There were 4 patients with grade 3 or more toxicity of thrombocytopenia in the combination arm, but they all were able to tolerate it; none of them had to come off the drug because of thrombocytopenia.

In terms of other non-hematological toxicity, we are seeing some mild gastrointestinal toxicity, but they were all grade 1/2. [There were also] some alterations in taste in a very small number of patients. So surprisingly, this combination of 2 therapies or the monotherapy was actually very well tolerated.

What’s interesting is that in both the combination arm and monotherapy arm, we are seeing responses in anemia, so we are seeing an improvement in hemoglobin. There were patients in the combination arm who became transfusion-independent when they were transfusion-dependent at baseline. This is very exciting. We are seeing some degree of improvement in splenomegaly across all patients, and we are also seeing improvements in symptom scores. Again, looking at all the hallmarks of MF treatment, we have seen some responses in all of these indicators.

In addition, we are seeing some improvement in bone marrow fibrosis in patients that we have sequential bone marrow [studies] of. Again, these are exciting results because it seems that this combination has an effect on the bone marrow environment of these patients.

TARGETED ONCOLOGY: Are there other agents that are currently being investigated in MF that could be useful in this patient population?

KremyanskayaIn MF, like I said earlier, there is only 1 approved medication, ruxolitinib. There are other JAK inhibitors that are in late-stage development that are going to be targeting, hopefully, different groups of patients. One of the potential toxicities of most JAK inhibitors is they cross cytopenias, specifically thrombocytopenia and anemia, so that can limit its use in patients that have low counts to begin with. That’s what often makes the patient have to come off this therapy, that they develop significant thrombocytopenia, for example.  The JAK inhibitors that are in late-stage development, for example fedratinib and pacritinib, and hopefully they will also be useful to these patients in different scenarios.

TARGETED ONCOLOGY: What would you say is the biggest challenge with MF?

KremyanskayaMF is a rare disease; patients who have it are in a difficult situation because the general population doesn’t know anything about these diseases. They can get sick, they can have a lot of problems both physically and emotionally, and there are not a lot of great treatment options available to them right now. There is a huge unmet need for new therapies that will either be second- or third-line for these patients after they fail approved therapies, or for specific patient populations, such as patients whose main issues are with anemia, for therapies that target different mechanisms of action and work differently.
 
 
Reference:
Kremyanskaya M, Hoffman R, Mascarenhas J, et al. A phase II study of cpi-0610, a bromodomain and extraterminal protein inhibitor (BETi) alone or with ruxolitinib (RUX), in patients with myelofibrosis (MF). J Clin Oncol. 2019;37(suppl; abstr 7056).


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