CPI-0610 as Monotherapy or With Ruxolitinib Appears Effective in Myelofibrosis

John O. Mascarenhas, MD

The oral bromodomain and extra-terminal domain (BET) inhibitor, CPI-0610, demonstrated spleen volume reduction (SVR), symptom improvement, and reduction in bone marrow fibrosis as monotherapy or in combination with the JAK inhibitor ruxolitinib (Jakafi) in patients with myelofibrosis (MF), according to results of the MANIFEST trial which were presented at the 2019 ASH Annual Meeting.

CPI-0610 in combination with ruxolitinib or as a monotherapy resulted in promising SVR and symptom improvement. Thirty-eight percent of patients in arms 1 and 2 achieved at least a 1-grade improvement in the bone marrow fibrosis score, with 10 of 12 improvements occurring within the first 6 months. Additionally, 55% of patients experienced an improvement in hemoglobin by at least a 1.5 g/dL without a blood transfusion 12 weeks prior to assessment.

The open-label, phase II MANIFEST trial evaluated CPI-0610 as monotherapy or in combination with ruxolitinib in patients with MF. In arms 1 and 2, patients with MF whose disease is resistant or intolerant to ruxolitinib received CPI-0610 as monotherapy or combined with ruxolitinib. Patients in arm 3 were JAK inhibitor naïve and received combination treatment.

In cohort 3, 80% of evaluable patients experienced SVR by at least 35%, and 71% of patients achieved at least 50% improvement in the Total Symptom Score (TSS) at 12 weeks. Twenty-five percent of patients in cohort 2a, which included those with transfusion dependence (TD), received the combination therapy and achieved SVR by at least 35% at 24 weeks. Additionally, 92% of evaluable patients had an SVR to some degree and 54% of patients experienced at least 50% improvement in the TSS.

In cohorts 1a, 1b, and 2b, SVR was achieved in 69% of evaluable patients in cohort 2b, 50% in cohort 1a, and 71% in cohort 1b. TSS by at least 50% was achieved in 38% of patients in cohort 2b, 0 in cohort 1a, and 60% in cohort 1b.

Six of 14 patients (43%) in cohorts 2a were converted from TD to transfusion independence (TI) with at least 24 weeks of treatment. Neither of the 2 patients who had TD in cohort 1a became TI with at least 24 weeks of treatment.

Overall, CPI-0610 was generally well tolerated. In arm 3, none of the adverse events (AEs) led to study discontinuation. The most common non-hematologic AEs included diarrhea, nausea, dizziness, and muscle spasms; however, these were all primarily grades 1 or 2. Three patients had grade 3 or greater anemia, and 1 patient had grade 4 thrombocytopenia, though it was reversible.

In arms 1 and 2, the combination was still well-tolerated. The most common hematologic AE was thrombocytopenia. Nine patients had at least grade 3 or higher thrombocytopenia, including 2 patients in arm 1 and 7 in arm 2. The most common non-hematologic AEs included diarrhea, nausea, cough, fatigue, vomiting, and upper respiratory tract infection and were primarily grades 1 and 2 in severity. Additionally, 8.9% of reported grade 4 AEs, though all were resolved.

In an interview withTargeted Oncology, John O. Mascarenhas, MD, a clinical investigator in myeloproliferative neoplasms, associate professor of medicine at the Icahn School of Medicine, and director of the Adult Leukemia Program at Mount Sinai in New York, discussed the phase II findings that demonstrated promising activity with CPI-0610 in a patient population of unmet need. He also shared his thoughts on the next steps necessary for moving CPI-0610 forward following these preliminary findings and how this agent could impact the treatment of patients with MF.

TARGETED ONCOLOGY: What was the rationale for evaluating CPI-0610 in combination with ruxolitinib in this study?

Mascarenhas:CPI-0610 is an oral BET inhibitor, and the rationale stems from work that came out of Memorial Sloan Kettering Cancer Center and The Ross Levine Lab, which showed a couple of things that were biologically important. The first was that JAK/STAT signaling, which is upregulated in MF, leads to epigenetic changes that affect the NF-kB pathway in this disease type. NF-kB is known to mediate the elaboration of co-inflammatory cytokines which contribute to the disease process and the symptom burden that plague patients with MF. 

[By these modalities, this emerges as] a viable therapeutic target, so a pan-BET inhibitor would make sense and is rational in this disease process. What we showed in an MPL-driven model of MF that either drug alone [or in combination] had some improvements in aspects of the disease in mice, but really it was the combination that was synergistic in improving blood counts, reducing spleen and marrow abnormalities, and extending survival. That set the stage for the trial evaluating CPI-0610, an oral BET inhibitor, in the phase II MANIFEST trial.

TARGETED ONCOLOGY: How was the trial designed?

Mascarenhas:We tested the drug at a dose of 100 mg once daily for 14 days in a row on a 21-day cycle. There are 3 patient [arms] that go into this study. They are all patients with MF that have either intermediate or higher MF risk by the Dynamic International Prognostic Scoring System. The first arm of patients who failed ruxolitinib, were intolerant to it, or were ineligible for ruxolitinib received monotherapy CPI-0610. The second arm was on ruxolitinib but did not have full benefit or had suboptimal response, so these patients had an add-on of CPI-0610 in combination with a stable dose of ruxolitinib. There was a third arm that included treatment-naïve patients who got both drugs upfront in combination.

The patient arms were also stratified [into cohorts] by whether patients had TD or TI. In the subgroups of patients who went into the trial with TD, the primary outcomes measure is primary TI; and in the patients who did not have TD, the primary outcome measure was SVR by 35% at 6 months, which is a standard MF response assessment measure.

TARGETED ONCOLOGY: What are the findings from this combination?

Mascarenhas:What this showed at the data cutoff is that there was activity with the drug as monotherapy in patients who were either relapsed/refractory or intolerant to ruxolitinib, both in terms of SVR and symptom burden, although it wass not dramatic. It clearly had activity that was demonstrated in this study. What is more impressive is that in patients who were failing ruxolitinib or had a suboptimal response, [the addition of] CPI-0610 was shown to dramatically salvage the situation in terms of improving DVR and symptoms, as well as converting patients from TD to TI. Out of 14 patients who were evaluable for conversion from TD to TI in the combination cohort, cohort 2a, 6 patients met the end point for TI.

I think that draws a lot of attention to this study because anemia is an unmet need in MF, [because] we don’t have that many great anemia drugs. Traditionally, erythropoietin or a combination with erythropoietin, immunomodulatory drugs, and even danazol can be used, to varying degrees, to get 20% to 40% response rates. However, they are not durable and have their own toxicity profiles. For patients that do not respond to those drugs, there’s no great alternative. Luspatercept-aamt (Reblozyl) acts as a ligand trap that is under clinical investigation, but what is attractive about CPI-0610 is that it is oral and can be added to ruxolitinib to garner benefit from JAK inhibition. It works synergistically, and the toxicity profile is favorable. There were very infrequent grade 3/4 case of thrombocytopenia and anemia, and there were infrequent grade 3/4 gastrointestinal (GI) toxicities. Although there is some GI toxicity associated with this agent [that occur within] 2 weeks of when the drug is administered, they are manageable. That is the important part of the quality of this drug. It has activity across all spectrums of patients with MF who have failed [JAK inhibition]and are getting monotherapy or in combination with ruxolitinib.

There was also this group of patients who were ruxolitinib-naïve in arm 3. What is impressive about that is not only the depth of response, but the increase in responders. It has the ability to get much deeper spleen responses in far greater numbers of patients treated with the combination of these 2 drugs upfront. That may ultimately be where the benefit of CPI-0610 is, providing it earlier in the disease process with ruxolitinib in which there is potential to modify the disease in a more profound way than just JAK inhibition where you get deep spleen responses and symptom improvements. CPI-0610 has the potential for anemia responses that can be durable, but from a biomarker aspect, we also saw that you can attain bone marrow fibrosis reduction within a relatively short period of time, 6 months, on therapy in a significant proportion of patients that were treated with this drug. It seems to be an active drug. This is still early on in the development, and what is exciting is it continues to add to the accrual of the study. Ultimately, I hope [there] will be a phase III study in combination with ruxolitinib.

TARGETED ONCOLOGY: What do you think are the next steps for CPI-0610?

Mascarenhas:I’m looking forward to getting a broader experience with the drug because with the presentations that have already occurred and in relation to this study, there’s a lot of interest and increasing uptake in accrual. I think overtime with more experience, more investigators, and beyond the 90 patients we presented from arm 1, 2, and 3, there will be continued experience that will help clarify and confirm the responses we are seeing. Hopefully that will provide enough confidence to the company, investigators, and the community in general to take this into a phase III setting, which would probably compare combinations of ruxolitinib and CPI-0610 versus ruxolitinib and a placebo, but that would have to be determined.

TARGETED ONCOLOGY: What do you hope oncologists take away from these data?

Mascarenhas:The take home message is that particularly in a subset of patients that are having a suboptimal response to ruxolitinib and TI that this is an add-on strategy that can salvage spleen and symptoms responses, which are clearly effective in their improvement in the change score, and convert TD to TI in about 40% of patients. Patients are also obtaining bone marrow fibrosis reductions, so this suggests we are modifying the disease in a more profound way, and that’s exciting because that’s just the next step in improving outcomes in our patients.

TARGETED ONCOLOGY:What kind of impact do you think CPI-0610 can have in patients with MF in years to come?

Mascarenhas:If the study continues the way it has so far, I would hope it would continue on to a phase III study in a relatively short period of time, which would hopefully determine the synergy of the 2 drugs together. Perhaps particularly for patients with MF, which is a population of unmet need, [the trial] would show these spleen and symptom responses, as well as bone marrow fibrosis reduction, that would create a regulatory pathway to approval so that we could get this drug out to patients in the community. The JAK inhibition was a great first step in the armamentarium, but the median time to discontinuation is about 3 years. We know it affects the clonal disease process in a profound way, but patients can still progress, lose response overtime, and have evolution of disease. Other therapies that have biological rationale and preclinical evidence such as this BET inhibitor are warranted in this space where there are limited options for patients.

CPI-0610 will be a welcome addition. It’s an oral drug that is well-tolerated, so we can add it to ruxolitinib, which is attractive rather than its usual drug that requires you to be treating patients every couple of weeks, so that is another attractive option. One of the things we have not seen, which was a concern with this or any drug when we add to it, is added myelosuppression. In fact, we’ve seen minimal myelosuppression with significantly limited thrombocytopenia or anemia. It seems to be a drug that is definitely worth further evaluation, and it could be combined with ruxolitinib. I hope that’s a phase III study.

Reference:

Constellation Pharmaceuticals Provides Updates Preliminary Data from MANIFEST Clinical Trial with CPI-0610 in Oral and Poster Presentations at ASH [news release]. Cambridge, MA: Constellations Pharmaceuticals; December 9, 2019. https://www.globenewswire.com/news-release/2019/12/09/1958004/0/en/Constellation-Pharmaceuticals-Provides-Updated-Preliminary-Data-from-MANIFEST-Clinical-Trial-with-CPI-0610-in-Oral-and-Poster-Presentations-at-ASH.html. Accessed December 9, 2019.