NF-kB has been found to be constitutively activated in many lymphomas, such as diffuse large B-cell lymphomas (DLBCL), particularly the ABC subgroup. In preclinical studies, CPI-0610, a BET specific small molecule inhibitor, results in downregulation of NF-κB signaling activity, accompanied by loss of viability of ABC-DLBCL cell lines. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883).
Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225 (tablets) administered orally QD on a 14 day on, 7 days off schedule were evaluated. The primary objective was to determine the maximum tolerated dose (MTD) and key secondary objectives were to determine the pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of CPI-0610.
64 patients were enrolled (56% DLBCL) with a median of 4 prior lines of therapy. MTD for this trial was 225 mg QD tablets. Ten patients were treated at MTD with only 1 DLT (thrombocytopenia). The most frequent treatment related adverse events were thrombocytopenia (45%), fatigue (34%), nausea (27%) decreased appetite (27%) and anemia (25%). Thrombocytopenia, a class effect for all BET inhibitors, was dose limiting however, is was reversible (<1 week) and not cumulative. Five patients had an objective response; 2 CRs (1 T-cell/histocyte-rich DLBCL, 1 ABC-DLBCL), 3 PRs (1 follicular lymphoma, 2 ABC-DLBCL) and 5 patients had prolonged (> 6 months) SD. Three of the responses and 1 of the prolonged SD were in patients with ABC-DLBCL. PK was dose-proportional with Cmax reached after 3 hours and a half-life of 16 hours. PD analysis of BET target genes demonstrated dose dependent decreases in IL8 and CCR1 mRNA between 2-8 hours post dose.
CPI-0610 is a well-tolerated, oral BET inhibitor that has demonstrated anti-tumor activity in advanced lymphoma patients.
NCT01949883
Constellation Pharmaceuticals
Constellation Pharmaceuticals
J. Mertz, R. Sims: Constellation Pharma employee. F. Garner: Radius stock, Constellation Pharma employee. A. Senderowicz: Constellation Pharma employee, on the BOD of Puma Pharmaceuticals. All other authors have declared no conflicts of interest.
EZH2 is the catalytic subunit of the PRC2 complex, and plays an important role in transcriptional repression. EZH2 over-expression is correlated with poor prognosis. Hot spot mutations in EZH2 were first identified in GCB-DLBCL and follicular lymphoma (FL). CPI-1205 is a potent, selective, SAM-competitive EZH2 inhibitor. A Phase I study was conducted in B-cell lymphoma patients. Primary Objectives: Define maximum tolerated dose of CPI-1205 and the dose-limiting toxicities (DLTs).
CPI-1205 was given orally twice daily (BID, in 28-day cycles) in 4 dose cohorts: 200 [n = 4], 400 [n = 5], 800 [n = 10] and 1600 mg [n = 13]. Eligibility criteria included adults that had progressed on standard therapy, ECOG PS of 0-2, and adequate organ function. The PK and PD profiles were evaluated. Disease responses were determined using the 2014 Lugano Response Criteria.
32 pts were enrolled (22 escalation, 10 expansion): 17 DLBCL, 4 FL, 2 marginal zone lymphoma and 9 others. Median age: 63 yrs (29-80), 22 pts: male, median prior treatments: 3. Tumor EZH2 status was determined in 28 pts (n = 1 data pending, n = 3 tissue unavailable): wild-type=23 and mutations=5. While most drug-related adverse events were grade 2 or lower, the most common treatment-related adverse events (TRAEs) in ≥ 5% pts of any grade were nausea, diarrhea, anemia and fatigue. There were 7 patients with TRAEs ≥ grade 3, nausea (n = 1), lymphocyte count decreased (n = 3), anemia (n = 1), hypertension (n = 1) and toxic epidermal necrolysis (n = 1). No DLTs were reported. One pt had CR at cycle 6, 5 pts had SD (3 remained on SD ≥ 6 months) by investigator assessment. An ongoing central review imaging assessment underscored CR and PRs and will be presented at the meeting. The half-life of CPI-1205 was short (∼3 hours). Target engagement with CPI-1205 was demonstrated by assessing the reduction in H3K27me3 by IHC in skin and lymphoma tissue.
CPI-1205 is well tolerated with manageable toxicities with evidence of antitumor activity and target engagement. Based upon the safety profile/PD of CPI-1205, an expansion phase in GCB-DLBCL or FL with/out EZH2 mutation was initiated at 800 mg BID and subsequently TID. Additional trials using CPI-1205 in combination in solid tumors are ongoing.
NCT02395601
Constellation Pharmaceuticals
Constellation Pharmaceuticals
C. Lebedinsky, W.D. Bradley, P. Trojer: Shareholder and employee of Constellation Pharmaceuticals. A. Senderowicz: Employee and own stock options in Constellation Pharmaceuticals Member of Board of Director of Puma Biotech. All other authors have declared no conflicts of interest.
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The Institute of Cancer Research: Royal Cancer Hospital, London, UK
Cancer Research UK National Institutes for Health Research Biomedical Research Centres
All authors have declared no conflicts of interest.
G-quadruplexes are secondary DNA structures that reversibly form in guanine-rich regions that can lead to replication fork collapse and double-stranded DNA breaks. Preclinical work by our group has demonstrated that CX-5461 can stabilize G-quadruplexes, resulting in synthetic lethality in BRCA1/2 deficient cell lines and xenograft models.
We conducted a phase I study of 7 dose levels of CX-5461 (DLs: 50, 100, 150, 200, 250, 325, 475 mg/m2) administered intravenously on days 1 and 8 of a 4-week cycle in patients with advanced solid tumors with a PS 0-2 and adequate organ function using a 3 + 3 design. Patients were treated until disease progression. The primary objective was the determination of RP2D. The DLT evaluation period was cycle 1 and AEs needed to be maximally managed (i.e diarrhea, phototoxicity, nausea/vomiting) to be considered a DLT. Secondary objectives include ORR (RECIST 1.1), PK, and toxicity (CTCAEv4.0).
As of December 18th 2017, 24 patients have been treated (DL 0-3: 4 per cohort; DL 4-5: 3 per cohort; DL6: 2 enrolled). Twenty-four patients are evaluable for toxicity and PK while 20 patients are evaluable for response. Of the evaluable patients (n = 24), the median age is 56 with 16 patients having 3 or more prior regimens for their disease. There have been no DLTs observed to date. There were two treatment-related non-DLT grade 3 photosensitivity events (DL0, DL4) that were reversible and were secondary to lack of photo-protective measures. Treatment-related grade 1-2 AEs >10% were mucositis, nausea, dry eyes and hand-foot syndrome. Early PK results have shown non-proportional increases for Cmax and AUC24,∞. In terms of best response, one BRCA2 patient at DL2 obtained a PR with a 67% reduction in disease burden for a duration of 9.6 months. Five patients (4 BRCA1/2, 1 Li Fraumeni) obtained SD as best response.
CX-5461 is tolerable with preventable photosensitivity being the main toxicity observed. The RP2D has not yet been reached. Preliminary activity for CX-5461 has been observed in patients with HR-deficient tumors. Alternative dosing schedules are being evaluated. A phase II study for breast cancer patients with germline HR deficiency or tumor HRD aberrations is planned.
NCT02719977
Canadian Cancer Trials Group
Stand up to Cancer Senhwa Pharmaceuticals
J. Soong: Medical lead at Senhwa Biosciences for CX-5461. Employed by Senhwa Biosciences. S. Aparicio: Consultant with Senwha Biosciences. All other authors have declared no conflicts of interest.