Purpose: To determine the dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetics, and preliminary evidence of antitumor activity of CUDC-427 (formerly GDC-0917), a selective antagonist of inhibitor of apoptosis (IAP) proteins.

Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily 14-day on/7-day off schedule in 21-day cycles using a modified continuous reassessment method design. Blood samples were assayed to determine the pharmacokinetic properties, pharmacodynamic alterations of cellular IAP levels in peripheral blood mononuclear cells (PBMC), and monocyte chemoattractant protein-1 (MCP-1) levels.

Results: Forty-two patients received 119 cycles of CUDC-427. Overall, the most common treatment-related toxicities were fatigue, nausea, vomiting, and rash. One DLT (grade 3 fatigue) occurred in a patient at 450 mg dose level during cycle 1, and 5 patients experienced AEs related to CUDC-427 that led to discontinuation and included grade 3 pruritus, and fatigue, and grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg orally daily for 2 weeks was reached, which allometrically scaled to exceed the IC90 in preclinical xenograft studies. Significant decreases in cIAP-1 levels in PBMCs were observed in all patients 6 hours after initial dosing. Responses included durable complete responses in one patient with ovarian cancer and one patient with MALT lymphoma.

Conclusions: CUDC-427 can be administered safely at doses up to 600 mg daily for 14 days every 3 weeks. The absence of severe toxicities, inhibition of cIAP-1 in PBMC, and antitumor activity warrant further studies. Clin Cancer Res; 22(18); 4567–73. ©2016 AACR.

Translational Relevance

This study is the first report of the safety and feasibility of administering CUDC-427 (GDC-0917), a selective monovalent inhibitor of inhibitor of apoptosis (IAP) proteins. CUDC-427 at the dose and schedule determined in this study is safe and feasible, has demonstrated target engagement and inhibition in pharmacodynamic and translational studies, and demonstrated antitumor activity in two patients with molecular abnormalities that is linked to IAP activity in cancer.

Apoptosis is a physiologic cell death process that, at least in part, is responsible for normal tissue homeostasis and results in the removal of nonessential cells, including those with mutations or alterations in cell-cycle control. Malignant cells, unlike their normal counterparts, are under physiologic stress and are highly dependent on aberrations in the apoptosis signaling pathways to maintain viability.

CUDC-427 is a potent, oral, monovalent, and selective antagonist of the inhibitor of apoptosis (IAP) proteins. The IAP proteins confer protection from death-inducing stimuli by binding to, and inhibiting activated caspases that are critical for the execution of apoptosis (1–3). In contrast to other apoptotic pathway–targeting therapies, CUDC-427 promotes activation of the postmitochondrial downstream apoptotic pathways, creating a potential therapeutic intervention for tumors that exhibit resistance to chemotherapy and radiotherapy from a host of upstream aberrant apoptotic pathway alterations.

CUDC-427 demonstrated single-agent antitumor activity in mouse xenograft models bearing subcutaneous MDA-MB-231 tumors. In addition, CUDC-427 demonstrated additive activity in combination with chemotherapeutic agents and TRAIL receptor–targeting antibodies in xenograft tumor models. Preclinical safety and pharmacokinetic testing established an expected therapeutic range of doses as well as elucidated possible toxicities including inflammatory cytokine and chemokine proteins that could cause an inflammatory reaction and reversible mild to moderate inflammation in the lungs and liver.

The impetus for the clinical development of CUDC-427 included the critical role of apoptosis pathway aberrations in neoplasia and the aforementioned safety and antitumor activity of CUDC-427 in preclinical models. The objectives of this phase I first-in-human and pharmacokinetic study of CUDC-427 were to determine (i) the safety and tolerability of daily oral administration of CUDC-427; (ii) the dose-limiting toxicities (DLT) on a 14-day on/7-day off schedule; (iii) the pharmacokinetic and pharmacodynamic properties; and (iv) preliminary evidence of anticancer activity in patients with advanced solid malignancies and lymphomas.

Eligibility

Eligible patients had pathologically confirmed solid malignancies or lymphoma refractory to standard therapy or for which no standard therapy existed: age ≥18 years; life expectancy ≥12 weeks; an Eastern Cooperative Oncology Group performance status of 0 to 1; resting oxygen saturation ≥92% on room air; previous chemotherapy ≥4 weeks (2 weeks for hormonal or kinase inhibitors and 6 weeks for prior mitomycin C or a nitrosourea); hemoglobin ≥9 g/dL; absolute neutrophil count ≥1,500/μL; platelets ≥100,000/μL; creatinine ≤1.5× upper limit of normal (ULN), bilirubin ≤1.5× ULN; aspartate serum transaminase (AST), alanine serum transaminase (ALT) ≤3× ULN; absence of pregnancy; prothrombin time/international normalized ratio ≤ 1.5× ULN; and no coexisting severe medical conditions. Patients were excluded if they had a clinically significant history of pulmonary, renal, or cardiovascular disease; chronic liver disease, active hepatic infection, evidence of hepatic cirrhosis, current alcohol abuse, active infections with hepatitis B or C virus; untreated brain metastases, uncontrolled ascites, known human immunodeficiency virus, gastrointestinal bleeding within past 6 months, history of malabsorption, or history of QT prolongation. Patients gave written informed consent according to federal and institutional guidelines before treatment.

Study design

CUDC-427 was administered orally daily on a 14-day on/7-day off dosing schedule (21-day cycles), except for cycle 1, which used 24 days to permit detailed single-dose pharmacokinetic sampling on day 1 and subsequently restarted on day 4 through 18. The starting dose, 5 mg, represented one tenth the rat severely toxic dose in 10% of animals (STD10). Planned dose levels of 5, 10, 20, 40, 60, 90, 200, 300, 450, and 600 mg were examined using modified continuous reassessment method (mCRM) methodology. DLT was defined as any grade ≥3 nonhematologic toxicity and grade ≥4 hematologic toxicity except grade 3 nausea or vomiting or diarrhea responding to standard-of-care management, alopecia, and grade 3 fatigue lasting <72 hours. If one patient experienced DLT, the cohort was expanded to 6 patients. The MTD was defined during cycle 1 as the highest dose at which <33% patients experienced treatment-related DLT. Toxicity was graded according to the NCI's Common Toxicity Criteria, version 4.0.

Patients were evaluated for tumor response using CT or MRI per RECIST 1.1 criteria every 6 weeks (4). Patients received CUDC-427 until disease progression, intolerable adverse event (AE), or consent withdrawal.

Pretreatment and follow-up studies

Pretreatment evaluation included a complete history, physical examination, and routine laboratory studies, including a complete blood count (CBC), white blood count, chemistry (electrolytes, BUN, creatinine, uric acid, glucose, alkaline phosphatase, lactate dehydrogenase, ALT, AST, total bilirubin, calcium, total protein, albumin, cholesterol, and triglycerides), amylase, lipase, serum C-reactive protein (CRP), fibrinogen, urinalysis, pulse oximetry, diffusion capacity of the lung for CO (DLCO), electrocardiogram, relevant radiologic studies, and tumor markers. During the study, radiologic studies for disease status were repeated after every other cycle, and tumor response was assessed by RECIST v1.1.

Repeat safety examinations, including history, relevant physical exam, CBC, and blood chemistry, were collected weekly. Amylase, lipase, CRP, fibrinogen, and coagulation studies were performed on day 1 of each cycle.

Pharmacokinetics

Plasma samples for pharmacokinetic parameters and MCP-1 levels were collected on day 1 (predose, 0.5, 1, 2, 3, 6, and 9 hours); days 2, 3, 4 (predose day 4), and 11 (predose); day 17 (predose and 0.5, 1, 2, 3, and 6 hours after dosing); and days 18 and 24 (predose). Urine was collected on day 1 predose, 0 to 6 hours postdose, and 6 to 24 hours postdose. Serum pharmacokinetic parameters were estimated using noncompartmental methods with WinNonlin Professional (Pharsight Corp).

Pharmacodynamics

cIAP-1 levels in peripheral blood mononuclear cells.

Whole-blood samples were collected on day 1 (predose), 6 and 72 hours postdose, cycle1 day 18 (24 hours after day 17 dosing), and then predose on day 24. Detailed methods are described in the Supplementary Methods section.

Exploratory molecular genetic analysis of tumor biopsies.

Optional paired tumor biopsies were performed in consenting patients predose after 14 days of dosing on cycle 1 (day 18). Archived tumor specimens were obtained for molecular genetic characterization if available.

General

Forty-two patients, whose pertinent characteristics are displayed in Table 1, received a total of 119 cycles of CUDC-427 at doses ranging from 5 to 600 mg orally daily. The median number of cycles administered per patient was 2 (range, 1 to 15).

Table 1.

Patient characteristics

CharacteristicNumber of patients
Number of patients 42 
Median number of courses/patient (range) 2 (1–15) 
Median age (range) 60.5 (36–86) 
Performance status 
 0 21 
 1 21 
Males/females 22/20 
Previous therapy 
 Chemotherapy 42 
 Radiotherapy 23 
 Biologic therapy 21 
 Hormone therapy 12 
Median number of prior chemotherapy regimens (range) 3 (1–9) 
Tumor types 
 Breast 10 
 Colorectal 10 
 Prostate 
 Lung 
 Ovarian 
Bladder, esophageal, Kaposi sarcoma, dendritic cell sarcoma, appendiceal, unknown primary, leiomyosarcoma, MALT lymphoma, and ectodermal neuroendocrine 1 each 
CharacteristicNumber of patients
Number of patients 42 
Median number of courses/patient (range) 2 (1–15) 
Median age (range) 60.5 (36–86) 
Performance status 
 0 21 
 1 21 
Males/females 22/20 
Previous therapy 
 Chemotherapy 42 
 Radiotherapy 23 
 Biologic therapy 21 
 Hormone therapy 12 
Median number of prior chemotherapy regimens (range) 3 (1–9) 
Tumor types 
 Breast 10 
 Colorectal 10 
 Prostate 
 Lung 
 Ovarian 
Bladder, esophageal, Kaposi sarcoma, dendritic cell sarcoma, appendiceal, unknown primary, leiomyosarcoma, MALT lymphoma, and ectodermal neuroendocrine 1 each 

The mCRM specified 3 patients at dose level 1 and then a minimum of 2 patients at subsequent doses until the occurrence of a DLT or a non-DLT AE of interest. At cohort 5 (60 mg), 2 additional patients were entered to replace 2 nonevaluable patients (early progression and hypersensitivity). Six patients were entered at the 300 mg dose level to collect additional safety data after a grade 2 pneumonitis was observed in a patient in cycle 2. A DLT (grade 3 fatigue) in 1 patient and 1 patient nonevaluable due to disease progression necessitated expansion at the 450 mg dose level to 7 patients. At the 600 mg dose level, the allometrically scaled dose and target plasma concentrations exceeded the IC90 in preclinical models and dose escalation ceased. The dose escalation, as well as DLT rate as a function of dose, is summarized in Table 2.

Table 2.

Dose-escalation scheme with DLT as a function of dose and number of courses

GDC-0917Number of patients
Dose levelModifiedNumber of patients with DLT
(mg)NewTo levelaTotalNumber of coursesFirst courseAll coursesb
 12 0/3 0/3 
10  0/3 0/3 
20  12 0/3 0/3 
40  0/2 0/2 
60  0/5 0/5 
90  18 0/3 0/3 
135  18 0/4 0/4 
200 1a  0/3 1/4a 
300 1a  15 0/6 1/7a 
450  11 1/7 2/7 
600  0/3 0/3 
Total 42   119   
GDC-0917Number of patients
Dose levelModifiedNumber of patients with DLT
(mg)NewTo levelaTotalNumber of coursesFirst courseAll coursesb
 12 0/3 0/3 
10  0/3 0/3 
20  12 0/3 0/3 
40  0/2 0/2 
60  0/5 0/5 
90  18 0/3 0/3 
135  18 0/4 0/4 
200 1a  0/3 1/4a 
300 1a  15 0/6 1/7a 
450  11 1/7 2/7 
600  0/3 0/3 
Total 42   119   

aOne patient whose doses were dose reduced to the next lowest dose for DLT on courses beyond course 1.

bThe number of DLTs over all courses for cumulative safety at each dose level.

Safety

The principal toxicities related to CUDC-427 were mild to moderate in severity and included fatigue, nausea, vomiting, and rash. Severe (grade ≥ 3) toxicities were rare and included ALT and AST increase (2 patients each), anemia, fatigue, neutropenia, pruritus, pyrexia, and rash (1 patient each). The most frequent related AEs as a function of dose and grade are summarized in Table 3. Beyond the aforementioned single case of pneumonitis, none of the other 41 subjects had evidence of pneumonitis.

Table 3.

Treatment-related AEs, by grade, in ≥5% of subjects as a function of dose level

AE5 (n = 3)10 (n = 3)20 (n = 3)40 (n = 2)60 (n = 5)90 (n = 3)135 (n = 4)200 (n = 3)300 (n = 6)450 (n = 7)600 (n = 3)All (n = 42)
Fatigue 
 Grade 1         
 2        
 3         
Nausea 
 Grade 1        
 2        
Vomiting 
 Grade 1         
Rash 
 Grade 1           
 2           
 3           
Pruritus 
 Grade 1         
 2         
 3         
Constipation 
 Grade 1          
Anorexia 
 Grade 1          
ALT increase 
 Grade 1           
 2           
 3           
AST increase 
 Grade 1           
 2           
 3           
Anemia 
 Grade 1            
 2             
 3            
AE5 (n = 3)10 (n = 3)20 (n = 3)40 (n = 2)60 (n = 5)90 (n = 3)135 (n = 4)200 (n = 3)300 (n = 6)450 (n = 7)600 (n = 3)All (n = 42)
Fatigue 
 Grade 1         
 2        
 3         
Nausea 
 Grade 1        
 2        
Vomiting 
 Grade 1         
Rash 
 Grade 1           
 2           
 3           
Pruritus 
 Grade 1         
 2         
 3         
Constipation 
 Grade 1          
Anorexia 
 Grade 1          
ALT increase 
 Grade 1           
 2           
 3           
AST increase 
 Grade 1           
 2           
 3           
Anemia 
 Grade 1            
 2             
 3            

The specific rash related to CUDC-427 was characterized by faint, dry erythema distributed on the facial brow, bridge of the nose, malar eminence, and upper extremities, accompanied, in some cases, by pruritus.

Pharmacokinetic analysis

All patients had measurable plasma CUDC-427 concentrations with the pharmacokinetic parameters on days 1 and 17 listed in Table 4 and concentration–time profiles illustrated in Fig. 1. Following single-dose oral administration, CUDC-427 was rapidly absorbed, with peak concentrations (Cmax) generally occurring at 1 to 3 hours postdose. Mean half-life (t1/2) ranged from 3.95 to 7.56 hours across all dose cohorts. The parameters that reflect exposure (Cmax and AUC0-t) increased proportionally over the doses range examined. Consistent with the short terminal t1/2, accumulation of CUDC-427 in plasma was insignificant.

Table 4.

Pharmacokinetic parameters of GDC-0917 after a single dose (day 1) and at steady-state (day 17)

Cmax (ng/mL)AUC0-∞ (ng/mL*day)AUC0-24 (ng/mL*day)T1/2 (Hours)Tmax (Hours)Accumulation ratio
Dose level (mg/kg)No. of evaluable patientsDayMeanCV%MeanCV%MeanCV%MeanCV%MedianRangeMeanCV%
4.57 36.6 37.1 68.4 35.7 66.5 3.98 39.2 2–6 — — 
  17 8.44 58.1   76.2 36.1   1–3 1.61 1.2 
10 12.2 78.4 86.6 87.5 83.3 86.2 3.95 44.4 1–6 — — 
  17 8.37 59.7   103 56.6    0.97 13.2 
20 19.2 48.3 168 66.9 161 65.5 4.8 12.2 3–6 — — 
  17 21.6 26.3   145 44.1   2–3 0.99 21.1 
40 46.1 53.1 248 34.8 240 36.9 5.13 10.3  — — 
  17 37.4 29   237 18.2   1–2 1.03 19.3 
60 110 40.8 575 41.4 560 41.4 5.05 13.9 1–2 — — 
  17 74.8 21.3   474 26.0   1–2 0.93 25.2 
90 172 65.2 902 37.5 868 39.7 6.02 25.9 1–2 — — 
  17 222 38.1   1,030 29.4   1–2 1.29 39.6 
135 204 28.1 1,240 36.5 1,180 33.8 5.94 43 2–3 — — 
  17 284 18.9   1,330 28.0    1.14 7.84 
200 291 46.3 1,780 57.9 1,710 56.8 5.41 13.2  — — 
  17 264 17.8   1,980 28.4   2–6 1.37 50.6 
300 613 66.6 3,890 68.8 3,710 68.8 7.56 15.2 1–3 — — 
  17 551 45.1   3,710 34.0   1–3 1.54 72.6 
450 966 60.5 5,830 55.7 5,710 56.4 5.4 14.7 1–3 — — 
  17 796 56.3   5,120 52.9   1–3 0.77 14.3 
600 744 10.5 5,320 40.4 5,120 39.1 5.62 9.99  — — 
  17 957 43.5   7,000 79.0   2–6 1.24 40.3 
Cmax (ng/mL)AUC0-∞ (ng/mL*day)AUC0-24 (ng/mL*day)T1/2 (Hours)Tmax (Hours)Accumulation ratio
Dose level (mg/kg)No. of evaluable patientsDayMeanCV%MeanCV%MeanCV%MeanCV%MedianRangeMeanCV%
4.57 36.6 37.1 68.4 35.7 66.5 3.98 39.2 2–6 — — 
  17 8.44 58.1   76.2 36.1   1–3 1.61 1.2 
10 12.2 78.4 86.6 87.5 83.3 86.2 3.95 44.4 1–6 — — 
  17 8.37 59.7   103 56.6    0.97 13.2 
20 19.2 48.3 168 66.9 161 65.5 4.8 12.2 3–6 — — 
  17 21.6 26.3   145 44.1   2–3 0.99 21.1 
40 46.1 53.1 248 34.8 240 36.9 5.13 10.3  — — 
  17 37.4 29   237 18.2   1–2 1.03 19.3 
60 110 40.8 575 41.4 560 41.4 5.05 13.9 1–2 — — 
  17 74.8 21.3   474 26.0   1–2 0.93 25.2 
90 172 65.2 902 37.5 868 39.7 6.02 25.9 1–2 — — 
  17 222 38.1   1,030 29.4   1–2 1.29 39.6 
135 204 28.1 1,240 36.5 1,180 33.8 5.94 43 2–3 — — 
  17 284 18.9   1,330 28.0    1.14 7.84 
200 291 46.3 1,780 57.9 1,710 56.8 5.41 13.2  — — 
  17 264 17.8   1,980 28.4   2–6 1.37 50.6 
300 613 66.6 3,890 68.8 3,710 68.8 7.56 15.2 1–3 — — 
  17 551 45.1   3,710 34.0   1–3 1.54 72.6 
450 966 60.5 5,830 55.7 5,710 56.4 5.4 14.7 1–3 — — 
  17 796 56.3   5,120 52.9   1–3 0.77 14.3 
600 744 10.5 5,320 40.4 5,120 39.1 5.62 9.99  — — 
  17 957 43.5   7,000 79.0   2–6 1.24 40.3 

Abbreviations: AUC0-∞, area under the concentration time curve from 0 to infinity; AUC0-24, AUC from 0 to 24 hours; Cmax, maximum observed plasma concentration;

CV, coefficient of variation; Tmax, time to maximum observed plasma concentration; T1/2, elimination half-life.

Figure 1.

Cycle 1 mean plasma concentration–time profiles of CUDC-427 after single dose (day 1).

Figure 1.

Cycle 1 mean plasma concentration–time profiles of CUDC-427 after single dose (day 1).

Close modal

Pharmacodynamic analysis

cIAP-1 levels in peripheral blood mononuclear cells and tumor specimens.

Statistically significant decreases in cellular cIAP-1 were measured in peripheral blood mononuclear cells (PBMC) samples from all patients on the study 6 hours after cycle 1 day 1 dosing of CUDC-427, regardless of dose level, although greater diminution (>90%) occurred consistently at doses that equaled or exceeded 300 mg (Table 5). Partial recovery of cIAP1 levels were observed by day 4 (after no treatment days 2 and 3) but remained below baseline levels. After 14 days of continuous dosing, cIAP-1 levels were significantly decreased from baseline, with many patients having undetectable cIAP-1 protein, and levels recovered only after the 1-week dose holiday (prior to cycle 2 day 1, data not shown). Four patients underwent optional paired tumor biopsies for cIAP-1 levels. In 2 patients, the tumor specimens were insufficient for analysis, whereas in 2 patients with sufficient paired tumor specimens, cIAP-1 levels decreased 75% of predose concentrations consistent with target activity of CUDC-427.

Table 5.

Mean percent reductions in cIAP-1 protein levels in MNCs as a function of dose level and time point

Dose level (# Pts)Median percent reduction (range) 6 h post doseMedian percent reduction (range) 72 h post dose recovery phaseMedian percent reduction (range) 14 days continuous dosing
5 (3) 81 (42–100) 41 (10–44) 69 (68–100) 
10 (3) 76 (55–87) 18 (−5–62) 49 (31–66) 
20 (3) 78 (75–86) 54 (43–68) 72 (71–85) 
40 (2) 64 (39–90) 36 (25–46) 90 (87–92) 
60 (6) 99 (99–99) 43 (−2–63) 94 (93–97) 
90 (2) 92 (88–96) 55a 88 (78–97) 
135 96 (43–100) 33 (−210–48) 94 (83–100) 
200 89 (87–97) 43 (43–49) 93 (50–95) 
300 92 (84–100) 66 (56–98) 100 (−68–100) 
450 100 (31–100) 41 (−6–82) 86 (60–100) 
600 94 (92–100) 67 (64–70) 91 (91–100) 
Dose level (# Pts)Median percent reduction (range) 6 h post doseMedian percent reduction (range) 72 h post dose recovery phaseMedian percent reduction (range) 14 days continuous dosing
5 (3) 81 (42–100) 41 (10–44) 69 (68–100) 
10 (3) 76 (55–87) 18 (−5–62) 49 (31–66) 
20 (3) 78 (75–86) 54 (43–68) 72 (71–85) 
40 (2) 64 (39–90) 36 (25–46) 90 (87–92) 
60 (6) 99 (99–99) 43 (−2–63) 94 (93–97) 
90 (2) 92 (88–96) 55a 88 (78–97) 
135 96 (43–100) 33 (−210–48) 94 (83–100) 
200 89 (87–97) 43 (43–49) 93 (50–95) 
300 92 (84–100) 66 (56–98) 100 (−68–100) 
450 100 (31–100) 41 (−6–82) 86 (60–100) 
600 94 (92–100) 67 (64–70) 91 (91–100) 

aOnly 1 specimen collected at this time point.

MCP-1, TNFα, IL6, IL8, and IFNγ plasma levels.

Blood specimens were analyzed for MCP-1, TNFα, IL6, IL8, and IFNγ. There was a trend toward higher plasma concentrations of MCP-1 at 9 hours after a single dose and 6 hours after 14 daily doses of CUDC-427, although there were no statistically significant changes in plasma MCP-1 observed in response to higher CUDC-427 dose cohorts. In addition, there were no statistically significant changes to plasma concentration of TNFα, IL6, IL8, and IFNγ in response to CUDC-427 treatment (data not shown).

Antitumor activity

Thirty-six patients with diverse malignancies were evaluable for response and 2 patients had evidence of a complete response (CR). The remainder of the 34 patients did not have an objective response.

One patient at the 300 mg dose level with a mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach had a CR on PET after 3.4 months of study treatment, remained on treatment for 5 cycles completing treatment with a sustained CR, and is alive without treatment 2+ years after discontinuing CUDC-427 without evidence of disease recurrence.

Another patient with a BRCA1 mutation (germline) and platinum-refractory ovarian cancer with biopsy-proven recurrent peritoneal disease had a CR of visible disease 6 weeks after beginning therapy at 450 mg dose level. The patient only received 4 cycles, two of which required 2 dose reductions due to severe rash, mucositis, and neutropenia before discontinuing due to AEs. Despite discontinuing CUDC-427, the patient sustained a CR for 18 months before relapsing in the original peritoneal site. This ovarian cancer patient experienced toxicities of greater severity, as well as some that were unique to this patient (mucositis, photosensitivity with generalized rash, and neutropenia), compared with other patients at the same or higher dose levels.

Abrogation of apoptosis is a hallmark of malignancies, yet despite the recognized importance in our understanding of cancer, there are currently no approved therapies that directly target the apoptosis-regulatory pathways.

In this study, CUDC-427 was well tolerated and could be safely administered to the highest planned dose level of 600 mg. At the three highest dose levels, a constellation of mild or modest nonhematologic AEs occurred and included fatigue, nausea, vomiting, and rash. One DLT grade 3 fatigue was observed at the 450 mg dose during cycle 1, with additional toxicities in another patient (BRCA1 ovarian) requiring dose reduction on subsequent cycles. Cumulative but reversible toxicities, although not dose limiting, included fatigue, rash, and pruritus, were important and did contribute to the 2 patients who discontinued even though they were responding to treatment. Abnormal liver function tests occurred in 11.9% of patients; none of these met Hy law criteria for idiosyncratic, potentially fatal liver disease.

In general, the AUC and Cmax values were dose proportional up to 600 mg and accumulation was insignificant. The pharmacokinetic profile for CUDC-427 behaved predictably, and concentrations could be achieved at dose levels that exceeded those that predicted antitumor activity in preclinical models. The highest planned dose of 600 mg achieved in this study exceeded the IC90 of CUDC-427 in preclinical models.

Pharmacodynamic studies confirmed target engagement with the 3 highest dose levels of CUDC-427 profoundly inhibiting cIAP-1 protein levels in PBMCs, and in many patients, below the level of detection for this assay. The inhibitory effect persisted, albeit to a lesser degree, for 72 hours after discontinuation of the study drug.

The profound activity observed in 2 patients with CRs that were durable warrants further study of this drug in selected indications and patients. MALT lymphoma is characterized by several genomic events including trisomy 3, 7, 12, 18, and disease-specific translocations of t(1:14)(p22;q23), t(14;18)(q32;q21), t(8:11)(q21;q21), and t(3;14)(p13;q32). Many of these trisomies and translocations involve the activation of NF-κB, which regulates the expression of genes implicated in the survival and proliferation, including BIRC3 and MALT1, of B cells (5, 6). In the patient that responded, molecular analysis did not reveal the aforementioned translocations but rather gene amplification in the genes for BIRC3 and MALT1 genes by array CGH. In contrast, the ovarian cancer patient who experienced a CR, but also had profound normal tissue toxicity, had a germline BRCA1 mutation. BRCA1 has been linked to aberrant apoptosis execution through the regulation of SIRT1, a regulator of survivin and the apoptosis pathway (7, 8). This finding raises the question whether cIAP-1 inhibition in normal tissues bearing the BRCA1-inactivating mutation was responsible for the toxicities observed.

Further work with CUDC-427 has begun utilizing continuous dosing schedules as well as exploration in the non-Hodgkin lymphoma indication. IAP inhibitors in general may have the greatest utility in combination with apoptosis-inducing agents. Preclinical data indicate that CUDC-427 can be combined and enhances antitumor activity with cytotoxics and TRAIL-targeting agents (Curis and Genentech unpublished data).

In conclusion, CUDC-427 can be safely administered to patients with advanced malignancies at doses up to 600 mg orally daily for 14 days every 3 weeks, attains plasma concentrations that exceed the IC90 in preclinical models, profoundly decreases cIAP-1 protein levels, and demonstrated promising durable CR in 2 patients.

A. Tolcher is an employee of Symphogen and is a consultant/advisory board member for Akebia, AP Pharma, Arqule, Asana, Astex, Bayer Schering Pharma, Bind, Blend, Celator, Dicerna, Eli Lilly, Endocyte, Genmab, Heron, Idea Pharma, Janssen, Johnson & Johnson, LiquidNet, MedImmuner, Mersana, Merus, Nanobiotix, Pharmacylics, Pierre Fabre, Symphogen, Proximagen, Valent, and Upsher-Smith. N. Budha and M. Mamounas have ownership interest (including patents) in Roche. No potential conflicts of interest were disclosed by the other authors.

Conception and design: A.W. Tolcher, H.A. Burris, W.J. Fairbrother, H. Wong, N. Budha, M. Mamounas, S. Royer-Joo, R. Yu, C.C. Portera, J.R. Infante

Development of methodology: A.W. Tolcher, H.A. Burris, H. Wong, W.C. Darbonne, R. Yu, C.C. Portera, J.R. Infante

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.W. Tolcher, J.C. Bendell, K.P. Papadopoulos, H.A. Burris, A. Patnaik, W.C. Darbonne, F. Peale, J.R. Infante

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.W. Tolcher, H.A. Burris, A. Patnaik, H. Wong, N. Budha, R. Yu, J.R. Infante

Writing, review, and/or revision of the manuscript: A.W. Tolcher, J.C. Bendell, K.P. Papadopoulos, H.A. Burris, A. Patnaik, W.J. Fairbrother, H. Wong, W.C. Darbonne, S. Royer-Joo, R. Yu, J.R. Infante

Study supervision: A.W. Tolcher, H.A. Burris, M. Mamounas, C.C. Portera, J.R. Infante

This trial was sponsored by Genentech Inc: ClinicalTrials.gov ID, NCT: 01908413.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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