Some recent papers on Constellation's CPI-0610 and Oncoethix's OTX-015 that I've cited below and pulled out the relevant details regarding toxicities found in animal or human studies. As described in slide 7 of the Zenith corporate update, CPI-0610 and OTX-015 are both first-generation reversible, pan BET inhibitors. On this same slide it states that several 2nd generation BET inhibitors from Bayer, Gilead, BMS, Incyte, Abbvie have a cleaner safety profile and also categorizes Zenith's program as a third generation BET inhibitor program. The hope, and expectation, is that these 2nd and 3rd generation BET inhibitors achieve their anti-cancer, anti-inflammatory, or other desired effects: 1) at lower doses; 2) with less side effects; and 3) without a need for intermittent treatment interruption to recover from side effects.

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.

Already in clinical trials, Constellation's CPI-0610 is a reversible, pan BET inhibitor. In addition to other data characterizing CPI-0610, they report in this paper some toxicity studies that were conducted in rat and dog, in which they administered the CPI-0610 once daily for 14 consecutive days as part of a dose range-finding study as well as in some repeat dosing studies followed by a 2-week recovery period. They observed a common set of toxicities in both rat and dog: "lymphoid depletion; hypocellularity of the bone marrow with associated anemia and thrombocytopenia; GI mucosal atrophy, erosion, and ulceration; degeneration of the testicular seminiferous epithelium; and mild to moderate hyperglycemia." Most of these toxicities were reversible after the 2-week recovery periods, with the exception of the testicular findings, which may require more tiem for recovery. In the conclusion of this paper, they describe this as an "acceptable toxicity profile in rat and dog."

Already in clinical trials, Oncoethix's OTX-015 is another reversible, pan BET inhibitor. Three recent papers below highlight the toxicites found in their Phase I human trials.

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628.

• From the abstract, "The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia."
• Patient 1: "The main side effects included fatigue and headache (grade 1) and reversible thrombocytopenia (grade 3), the latter necessitating ad hoc treatment interruptions (1 to 2 weeks) from cycle 3, and dose reduction to 60 mg QD from cycle 9."
• Patient 2: "Treatment was complicated by nausea, dysgueusia, anorexia, hyperglycemia (all grade 2) and thrombocytopenia (grade 3). OTX015/MK-8628 was interrupted during cycle 2 for non-hematologic toxicity and the dose was reduced to 60 mg QD from cycle 3."
• Patient 3: "Treatment was interrupted for 5 days after the first two weeks due to nausea and fatigue (grade 2) with worsening dyspnea. Nausea and fatigue improved to grade 1 while dyspnea returned to baseline levels...... Treatment was resumed at 60 mg QD........Cycle 3 was marked by grade 2 nausea and fatigue and treatment was discontinued at the end of this cycle"

Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study

"Findings

Between Feb 4, 2013, and Sept 5, 2014, 45 patients (33 with lymphoma and 12 with myeloma), with a median age of 66 years (IQR 55-72) and a median of four lines of prior therapy (IQR 3–5), were enrolled and treated. No DLTs were observed in the doses up to and including 80 mg once a day (first three patients). We then explored a schedule of 40 mg twice a day (21 of 21 days). DLTs were reported in five of six patients receiving OTX015 at this dose and schedule (all five patients had grade 4 thrombocytopenia). We explored various schedules at 120 mg once a day but none was tolerable, with DLTs of thrombocytopenia, gastrointestinal events (diarrhoea, vomiting, dysgeusia, mucositis), fatigue, and hyponatraemia in 11 of 18 evaluable patients. At this point, the Safety Monitoring Committee decided to establish the feasibility of 80 mg once a day on a continuous basis, and four additional patients were enrolled at this dose. DLTs (grade 4 thrombocytopenia) was noted in two of the patients. In light of these DLTs and other toxicities noted at 120 mg, the dose of 80 mg once a day was selected, although on a schedule of 14 days on, 7 days off. Common toxic effects reported in the study were thrombocytopenia (43 [96%] patients), anaemia (41 [91%]), neutropenia (23 [51%]), diarrhoea (21 [47%]), fatigue (12 [27%]), and nausea (11 [24%]). Grade 3–4 adverse events were infrequent other than thrombocytopenia (26 [58%]). OTX015 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Trough concentrations increased less than proportionally at lower doses, but reached or exceeded the in-vitro active range at 40 mg twice a day and 120 mg once a day. Three patients with diffuse large B-cell lymphoma achieved durable objective responses (two complete responses at 120 mg once a day, and one partial response at 80 mg once a day), and six additional patients (two with diffuse large B-cell lymphoma, four with indolent lymphomas) had evidence of clinical activity, albeit not meeting objective response criteria.

Interpretation

The once-daily recommended dose for oral, single agent oral OTX015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. OTX015 is under evaluation in expansion cohorts using this intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects."

Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study

"Findings

Between Jan 18, 2013, and Sept 9, 2014, 41 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 160 mg/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 120 mg doses hampered patient compliance and 80 mg once a day was judged the recommended dose with a 14 days on, 7 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 120 mg/day with trough concentrations in the in-vitro active range from 80 mg/day (274 nmol/L). Three patients (receiving 40 mg/day, 80 mg/day, and 160 mg/day) achieved complete remission or complete remission with incomplete recovery of platelets lasting 2–5 months, and two additional patients had partial blast clearance. No predictive biomarkers for response have been identified so far.

Interpretation

The once-daily recommended dose for oral, single agent oral OTX015 use in patients with acute leukaemia for further phase 2 studies is 80 mg on a 14 days on, 7 days off schedule."