Experience with the Combination of a Hypomethylating Agent and Valproic Acid in Pediatric Acute Myelogenous Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4036-4036
Author(s):  
Michael Rytting ◽  
Patrick Zweidler-McKay ◽  
Yang Hui ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero

Abstract Combination epigenetic therapy consists of the combination of a hypomethylating agent (5-aza-2′-deoxycitidine [decitabine] or 5-azacitidine) with a histone deacetylase (HDAC) inhibitor. We have performed two studies combining either decitabine (n=55) or 5-azacitidine (n=54) with valproic acid (VPA). VPA is a neurotropic agent with weak HDAC inhibitory capacity in the mM range. Both studies were open to children with relapsed or refractory AML age 2 or older. Of the 109 patients, 10 (9%) were considered pediatric patients (pts). Seven patients were treated with a fixed dose of intravenous decitabine (DAC) and escalating doses of VPA, and three patients were treated with 5-azacytidine, VPA and all-trans retinoic acid (ATRA). All of the pediatric pts were refractory to a minimum of two chemotherapy regimens for AML or had multiple relapses of AML. The median age was 17 (range 5–21), 5 (50%) were diploid, and the median WBC at presentation was 3.4 (range 0.9 to 16.3). Five of the 10 pts derived benefit from the combination. In the DAC plus VPA trial, three pts achieved a complete marrow response, defined as a hypocellular marrow with less than 5% blasts without recovery of peripheral counts. An additional pt had a partial response with 6% marrow blasts after therapy and improvement in transfusion requirements. In the 5AZA/VPA/ATRA trial, 1 complete marrow response was observed. No complete remission (CR) was observed. No differences were observed in terms of LINE methylation (measured using a bisulfite pyrosequencing assay) pretreatment in pediatric versus adult patients (44.7% [40–65] pediatric versus 46.3 [37–65] adult, p=0.3) or after therapy with the combination treatment. There was a trend towards higher bound VPA levels in the adult group on days 5 or 7 (median 72 [0–202] in adult versus 32 [2–114], p=0.49). Pediatric pts treated with DAC/VPA had less acetylation compared to adult pts (14% vs 35%) and showed no evidence of mRNA activation of p21. Overall, administration of DAC/VPA or 5AZA/VPA/ATRA was safe with no grade 3 or 4 toxicity and no induction mortality in the pediatric group. Combination epigenetic therapy has potential clinical activity in pediatric pts with highly pre-treated relapsed or refractory AML and should be studied in pediatric specific clinical trials.

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3271-3279 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hagop M. Kantarjian ◽  
Blanca Sanchez-Gonzalez ◽  
Hui Yang ◽  
Gary Rosner ◽  
...  

Abstract We conducted a phase 1/2 study of the combination of 5-aza-2′-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m2 by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks. This trial was registered at www.clinicaltrials.gov as #NCT00075010.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1955-1955 ◽  
Author(s):  
Jeffrey Lancet ◽  
Judith E. Karp ◽  
Larry D. Cripe ◽  
Gail J. Roboz ◽  
Matt Suster ◽  
...  

Abstract Background: Voreloxin (formerly SNS-595) is a first-in-class replication-dependent DNA damaging agent that causes apoptosis by DNA intercalation and inhibition of topoisomerase II. A previous phase 1 study of single-agent voreloxin demonstrated acceptable safety and strong signs of clinical activity in patients with relapsed/refractory hematologic malignancies (ASH 2007), where MTD was found to be 72 mg/m2 weekly x 3 and 40 mg/m2 twice weekly x 4. In nonclinical models, the combination of voreloxin and cytarabine demonstrated enhanced activity. Preliminary results of an ongoing phase 1b study of combination voreloxin plus cytarabine in relapsed/refractory AML patients are reported. Objectives: establish safety, tolerability and MTD of escalating doses of voreloxin combination with continuous infusion cytarabine, characterize voreloxin PK in the setting of cytarabine given as a continuous intravenous infusion (CIV) assess clinical activity explore markers of patient response evaluate ex vivo voreloxin sensitivity in bone marrow as a predictor of response. Methods: Open label, doseescalation phase 1b study with a starting dose of voreloxin of 10 mg/m2 (given on days 1,4) in combination with 400 mg/m2/day CIV cytarabine for five days. Dose-limiting toxicities (DLTs) were assessed during cycle 1. PK analyses for voreloxin were performed during cycle 1. Pre- and post-dose PBMC were obtained to evaluate modulation of DNA damage response markers as correlates of patient response. Ex vivo sensitivity to voreloxin of baseline bone marrow samples was evaluated using the CellTiter-Glo® proliferation assay. Clinical response was determined based on IWG criteria. Patients could receive up to 2 courses of induction, and patients achieving CR or CRp could receive up to 2 courses as consolidation. At MTD, an additional cohort of patients will be enrolled to further assess safety. Results: To date, 26 patients have been enrolled and 24 have received treatment. Demographics: 16 males, 8 females, median age 61.4 years (range 30 – 74.5 yrs). Disease status: 17 of 24 treated patients had relapsed disease. Median number of prior therapies was 2 (Range 0–4). Two patients had prior allogeneic stem cell transplant. Dose escalation has proceeded to 80 mg/m2/dose (cohort 6). Safety: a single DLT has been observed (grade 5 septic shock in one patient treated at 70 mg/m2). Grade 3+ related non hematologic AEs ≥ 5% incidence: infections (23%). Grade 3+ hematologic toxicities have been consistent with past experience and include febrile neutropenia, anemia, and thrombocytopenia. The most common reason for early study termination was disease progression. Voreloxin pharmacokinetics were unaffected by cytarabine compared with the single agent phase 1 study. Preliminary clinical responses are listed below in Table 1. Conclusion: Voreloxin given in combination with continuous infusion cytarabine is generally well-tolerated, with encouraging signs of activity in patients with relapsed/refractory AML. Dose escalation continues. Table 1: Clinical Responses by Cohort Cohort Voreloxin Dose Treated/Enrolled DLTs Responses 1 10 4/4 0 0 2 20 3/4 0 1 CR 3 34 4/4 0 2 CR 4 50 6/6 0 2 CR 5 70 7/8 1 2 CR


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3820-3820
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
...  

Abstract Abstract 3820 Background: DNA topoisomerase I (TopoI) is an essential mammalian nuclear enzyme that relaxes DNA supercoiling generated by transcription, replication and chromatin remodeling. Topotecan and other Topo I inhibitors have shown clinical activity in MDS and CMML. AR-67 [(20S)-7-tert-butyldimethysilyl-10-hydroxycamptothecin] is a third generation camptothecin analog that effectively inhibits topoisomerase I enzyme. Aim: This phase II study was conducted to estimate the efficacy and toxicity of AR-67 in patients with MDS, CMML or MDS/MPD who have failed prior therapies. Method: Subjects with MDS (>5% blasts, or IPSS risk group intermediate-1, intermediate-2 or high risk), CMML or MDS/MPD who had failed or were unable to receive therapy with either a hypomethylating agent (alone or in combination) or patients with abnormalities in chromosome 5q who failed either a hypomethylating agent or lenalidomide were eligible. Patients with performance status 0–2 with adequate organ function and no active, uncontrolled intercurrent illness or infection, receive AR-67 IV at 7.5 mg/m2 for 5 consecutive days every 4 weeks. Results: 10 patients with MDS, CMML or MDS/ MPD were enrolled (6 MDS, 2 CMML and 2 MDS/MPD). The median age was 69 years (yrs) (range, 52–83 yrs). All patients had received prior therapy with hypomethylating agents. The most common prior therapies included: azacytidine (n=6), decitabine (n=5) and clofarabine (n=5); either alone or in combination. The median number of prior therapies was 2 (range 1 to 4). Of the 6 MDS patients; 4 were IPSS Int-2 and 2 were IPSS Int-1. Both CMML patients were CMML-2. Cytogenetics analysis showed diploid karyotype in 4, trisomy 21 in 2, chromosome 7 abnormalities in 1, and various other abnormalities in 3. Molecular analysis showed NRAS mutation in 3 and FLT-3 ITD mutation in 1 patient. No patients had mutations in c-Kit, JAK-2 or NPM1. 9 of 10 enrolled patients received at least 1 dose of the AR-67. One patient was enrolled but withdrew prior to initiation of therapy. Median number of cycles received was 2 (1–6). Of the 9 patients treated, 1 patient had hematological response per IWG criteria. The hemoglobin improved from 8.1 g/dl to 11.5 g/dl, platelet count improved from 47 K/μL to 81 K/μL, peripheral blast count decreased from 4% to 1% and bone marrow blast count decreased from 9% to 5%. The response lasted 170 days. This patient also had a significant improvement in clinical manifestations associated with CMML, including fatigue, and incapacitating arthralgias allowing him to return to work. Two other patients had stable disease over 3 months and 2 months; respectively. The most common drug related adverse events were thrombocytopenia (5 overall; 3 grade 1–2; 2 grade 3), neutropenia (5 all grade 1–2), and anemia (5 all grade 1–2). Other noted adverse effects were diarrhea (4 overall; 3 grade 1–2, 1 grade 4), nausea (2 overall; 1 grade 2, 1 grade 3), elevated uric acid (2 overall; 1 grade 2, 1 grade 3), possible typhlitis (1 grade 3), mucositis (1 grade 1) and fatigue (1 grade 3, 1 grade 1). Dose reduction from 7.5 mg/m2 to 6.3 mg/m2 was required in 2 patients due to grade 3 fatigue and grade 3 thrombocytopenia; respectively. Conclusion: AR-67 administered at 7.5 mg/m2 showed efficacy and was tolerable in subjects with previously treated MDS, CMML or MDS/MPD. Myelosuppression is the most common toxicity, but is usually manageable. Additional studies of AR-67 in these disease groups are warranted. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1266-1269 ◽  
Author(s):  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
Manuel Aivado ◽  
Alf Bernhardt ◽  
Barbara Hildebrandt ◽  
...  

Abstract Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro. We treated 18 patients with myelodysplastic syndromes (MDS) and AML secondary to MDS (sAML/MDS) with VPA monotherapy (serum concentrations 346-693 μM [50-100 μg/mL]). Five patients received VPA and ATRA (80 mg/m2/d, days 1-7, every other week). Response according to international working group (IWG) criteria was observed in 8 patients (44%) on VPA monotherapy, including 1 partial remission. Median response duration was 4 months (range, 3-9 months). Four of 5 patients relapsing were treated with VPA + ATRA, 2 of them responding again. Among 5 patients receiving VPA + ATRA from the start, none responded according to IWG criteria, but 1 patient with sAML/MDS achieved a marked reduction in peripheral and marrow blasts. Thus, VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.


Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2302-2308 ◽  
Author(s):  
Andres O. Soriano ◽  
Hui Yang ◽  
Stefan Faderl ◽  
Zeev Estrov ◽  
Francis Giles ◽  
...  

The combination of a DNA hypomethylating agent with a histone deacetylase inhibitor has synergistic antileukemia activity and may restore sensitivity to all-trans retinoic acid (ATRA). We conducted a phase 1/2 study of the combination of 5-azacitidine (5-AZA), valproic acid (VPA), and ATRA in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m2 daily for 7 days. VPA was dose-escalated and given orally daily for 7 days concomitantly with 5-AZA. ATRA was given at 45 mg/m2 orally daily for 5 days, starting on day 3. A total of 53 patients were treated. Their median age was 69 years (range, 5-84 years). The maximum tolerated dose of VPA in this combination was 50 mg/kg daily for 7 days. Dose-limiting toxicity was reversible neurotoxicity. The overall response rate was 42%. In previously untreated older patients, the response rate was 52%. Median number of courses to response was 1 (range, 1-3 courses). Median remission duration was 26 weeks, and median survival has not been reached. A significant decrease in global DNA methylation and induction of histone acetylation were achieved. VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15553-e15553
Author(s):  
Xiao-li Wei ◽  
Yang Zhang ◽  
Hongyun Zhao ◽  
Zhiqiang Wang ◽  
Yu-Hong Li ◽  
...  

e15553 Background: PD-1 antibody monotherapy has shown durable response in colorectal cancer (CRC) patients (pts) with microsatellite instability (MSI) high status, who account for only 10–15% of all CRC pts. Preclinical studies revealed that inhibition of MAPK pathway with MEK inhibitors can increase T-cell infiltration into tumors and therefore might enhance the antitumor activity of immune checkpoint inhibitor. Thus, this study was conducted to evaluate the safety and antitumor activity of SHR7390, a MEK1/2 inhibitor, plus camrelizumab (anti-PD-1) in pts with CRC. Methods: In this single-arm, open-label, phase I study, pts with treatment-refractory advanced or metastatic CRC were enrolled to receive SHR7390 in an accelerated titration scheme at doses of 0.125, 0.25, and 0.5 mg orally qd, plus camrelizumab at a fixed dose of 200 mg IV q2w. Eligible pts were given a single dose of SHR7390, observed for 7–10 days, and then treated continuously with SHR7390 and camrelizumab in 28-day treatment cycles until disease progression, intolerable toxicities, or withdrawal of consent. A recommended dose for expansion was determined based on the safety and tolerability of the dose escalation stage. The primary endpoints were dose limiting toxicity (DLT) and maximum tolerated dose (MTD). This study is registered with ClinicalTrials.gov, number NCT03182673. Results: At data cutoff on May 30, 2020, 22 pts were enrolled. The median follow-up duration was 6 months. Seven pts had received ≥3 lines of prior treatment. MSI status were available in 21 pts (MSS/MSI-L, n = 18; MSI-H, n = 3). There were two pts each in the SHR7390 0.125 and 0.25 mg cohorts, and 0.5 mg cohort was expanded to 18 pts. One DLT (grade 3 rash) was reported in a pt in the 0.5 mg cohort and the MTD was not reached. Grade 3–4 treatment-related adverse events (TRAEs) were rash (n = 4), increased lipase, oedema peripheral, face oedema, and anemia (n = 1 each). One pt reported a grade 5 TRAE (increased intracranial pressure). Five pts (23%) achieved partial response (0.125 and 0.25 mg cohorts, n = 1 each; 0.5 mg cohort, n =3), including one out of three pts with MSS/MSI-L & BRAF mutant tumors (response lasting 13 months), one out of 15 pts with MSS/MSI-L & BRAF wild type tumors (response lasting 8 months), and all three pts with MSI-H tumors (responses lasting 31, 11, and 10 months, respectively). Three pts with MSS/MSI-L achieved stable disease, and the overall disease control rate reached 36%. Conclusions: SHR7390 plus camrelizumab showed a tolerable safety profile. Preliminary clinical activity was reported regardless of BRAF and MSI status, and future studies are warranted to further evaluate these results. Clinical trial information: NCT03182673.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 160-160 ◽  
Author(s):  
Andres O. Soriano ◽  
Hui Yang ◽  
Weigang Tong ◽  
Stefan Faderl ◽  
William Wierda ◽  
...  

Abstract 5-azacitidine (5-AC), and its analogue 5-aza-2′-deoxycitidine (5-DAC), are DNA hypomethylating agents. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI). Hypomethylating agents and HDACI restore ATRA sensitivity in resistant cells. The combination of a hypomethylating agent with an HDACI is antileukemic in vitro. Based on this, and on a prior study of 5-DAC and VPA (Garcia-Manero, Blood, in press), we developed a phase I/II study of the combination of 5-AC, VPA and ATRA. Patients (pts) with high risk MDS (≥10% blasts); relapsed/refractory AML; and pts > 60 years with untreated disease and adequate renal, hepatic functions and performance status were eligible. A fixed-dose of 5-AC was used: 75 mg/m2 sq daily x 7. ATRA dose was: 45 mg/m2 PO daily x 5 starting on day 3 of 5-AC. The phase I followed a classic 3+3 design. The initial dose of VPA was 50 mg/kg PO daily x 7 concomitantly with 5-AC. Cycles were at least 21 days long. The phase II targets a response rate of ≥30% with stopping rules. Cohorts of 10 pts (max 40) are studied. Thirty one pts are evaluable. Median age is 60 years (5–78). All, but 2 pts with MDS, had AML. Median number of prior therapies was 2 (0–5). Twenty six pts (83%) had abnormal cytogenetics. During the phase I, at a VPA dose of 50 mg/kg, 1/6 pts developed grade 3 non-hematological toxicity; at 62.5 mg/kg, 2/7, and at 75 mg/kg, 3/6. The dose limiting toxicity (DLT) was neurotoxicity, confusion and somnolence. The MTD was 50 mg/kg daily x 7. Twelve pts are enrolled in the phase II. Of the 31 evaluable pts, 9 achieved CR (ANC 10 9/L, platelets 100 x 10 9/L, and marrow blasts ≤5%) and 3 a CRp (same criteria as of CR but without complete platelet recovery), overall response (OR)39%. The median number of courses to response was 1 (1–3). Nine responses occurred in 16 untreated pts, OR 56% (Table). Eighteen patients were treated at the MTD with 9 responses (50%). Cytogenetic responses were observed in all responding pts. To assess the hypomethylating effect of 5-AC, the LINE test was used. Median LINE methylation pretreatment was 62.5% (57–67%), declined to 58% by day 7 and returned to baseline by day 0 of next cycle (p<0.001). No significant difference was observed between responders and non responders. Eighteen pts had evidence of histone 3 and 4 acetylation (66%). VPA bound level on day 2 was 146 mcg/ml (95% CI 122–170) in responders and 103 mcg/ml (95% CI 88–118) in non-responders, p< 0.005. Analysis of gene re-expression and cell differentiation are ongoing. In conclusion, the combination of 5-AC, VPA and ATRA is safe. The MTD of VPA is 50mg/kg daily x 7. The DLT is neurotoxicity. The combination has significant clinical activity. An OR of 56% was observed in patients > 60 years with previously untreated AML/MDS. Histone acetylation and transient global hypomethylation are observed. Higher levels of VPA are found in responders. Based on prior CALGB experience (Silverman, ASH 2005), this combination appears to be more active than single agent 5-AC in AML. The study continues to accrue. Responses VPA (mg/kg) Number of Patients CR CRp OR% Courses to response Duration of response (months) 50 18 7 2 50 1(1–3) 2.6(0.5–3.2) 62.5 7 1 0 14 2 3.73+ 75 6 1 1 33 1 8.1(7–9.2+) Total 31 9 3 38 1(1–3) 2.9(0.5–9.2+) Untreated AML/MDS>60 years 16 7 2 56 1(1–3) 2.9 (0.5–9.2+)


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 473-473 ◽  
Author(s):  
C. Gambacorti-Passerini ◽  
H. Kantarjian ◽  
T. Bruemmendorf ◽  
G. Martinelli ◽  
M. Baccarani ◽  
...  

Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor. Biochemical assays have shown it to be up to 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation. Unlike imatinib, bosutinib does not exhibit significant inhibition of c-kit or platelet-derived growth factor receptor (PDGFR), which may result in a relatively favorable safety profile. This is an ongoing open-label study in patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase chronic myelogenous leukemia and (Ph+) ALL who failed prior imatinib therapy or other TKIs. Objectives are to assess safety and clinical activity of bosutinib. Pts receive bosutinib 500 mg/day. We report preliminary data for 57 pts, median age 54 yrs (range 22–83 yrs), 54% male. 23 pts (40%) were in AP, 15 (26%) in blast crisis (BC), 14 (25%) had Ph+ALL, and 5 (9%) were unclassified. Prior therapy included interferon (22 pts), imatinib (55 pts; data missing for 2 pts), dasatinib (17 pts), nilotinib (10 pts), stem cell transplant (5 pts). Overall median duration of bosutinib treatment was 2.7 mos (range 0.03–10.8 mos). Complete hematological response (CHR) was obtained in 7/25 evaluable pts (28%), including 4/14 (29%) pts with AP-CML, 2/8 (25%) pts with BC-CML, and 1/3 (33%) pts with Ph+ ALL. Among pts with no other TKI exposure, major cytogenetic responses (MCyR) were observed in 5/14 evaluable pts (36%), including 3/6 (50%) pts with AP-CML, 2/5 (40%) pts with BC-CML. Among pts with prior TKI exposure, 3/10 (30%) had MCyR, including 0/3 AP, 1/4 BP, and 2/3 ALL pts. Median time to MCyR was 8.9 weeks for pts previously exposed and 12 wks for unexposed to other TKIs. Duration of MCyR was 18 wks. 19 previously unexposed patients were evaluable for major molecular response. 4 (21%) had major molecular response, 3 (16%) of which were complete. Of 42 pts with samples tested for mutations, 13 different mutations were found in 20 pts (48%), including 5 cases of T315I. CHR occurred in 2/3 pts with P-loop mutations and 5/17 with non-P-loop mutations; MCyR occurred in 2/2 pts and 4/9 pts, respectively. Treatment was generally well tolerated in this cohort of heavily pretreated patients. The most common adverse events were gastrointestinal (diarrhea [56%], nausea [37%], vomiting [35%]) but these were usually grade 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 weeks of therapy. Grade 3–4 hematologic laboratory abnormalities reported included thrombocytopenia in 31 pts (59%), neutropenia in 20 pts (38%), and anemia in 13 pt (25%). Grade 3–4 non-hematologic toxicities were diarrhea (9%) and vomiting (9%). Fluid retention was reported in 8 pts (14%), including 2 cases (3%) of pleural effusion (grade 2 and 3). Both were considered unrelated to treatment. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations. Bosutinib has a favorable toxicity profile with a small number of pts experiencing hematologic toxicity and fluid retention, possibly due to the lack of c-kit inhibition and PDGFR inhibition, respectively.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 834-834 ◽  
Author(s):  
Patrick McKay Boland ◽  
Alan Hutson ◽  
Orla Maguire ◽  
Hans Minderman ◽  
Christos Fountzilas ◽  
...  

834 Background: Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody approved in RAS-wt metastatic colorectal cancer (mCRC). Pre-clinical data have suggested that cetuximab triggers immunogenic cell death and support an immunologic basis of activity. Small clinical data sets demonstrate that EGFR-based therapy preferentially increases TILs in colorectal hepatic metastases. This Phase Ib/II study was designed to assess the safety and clinical activity of cetuximab and pembrolizumab in metastatic colorectal cancer. Methods: Eligible pts were those with RAS-wt mCRC, ECOG performance status (PS) 0-2, with at least 1 prior line of therapy for advanced stage disease, and no prior treatment with an anti-EGFR antibody. The phase Ib study was designed as a safety lead-in with a de-escalation design. Pembrolizumab was administered at a fixed dose of 200 mg q3week with standard cetuximab dosing (400 mg/m2 loading dose, followed by 250 mg/m2 weekly). DLTs were defined as any ≥ grade 3 clinically significant toxicity which is possibly related and occurs within the first 6 weeks of therapy. For rash and hypomagnesemia only ≥ grade 4 toxicities were considered DLTs. Correlative serial biopsies were performed at baseline and at 9 weeks. Results: 9 patients, ages 33-73, were enrolled onto the Phase Ib study between 8/10/16 and 11/2/16. No DLTs were observed. The most common AEs of any cause observed were xerosis, dermatitis acneiform rash, hypomagnesemia, vomiting, and fatigue. ≥ Grade 3 toxicities were uncommon, but included hypomagnesemia (3), rash (1), urticaria (1), hypocalcemia (1), alk phos elevation (1), and ascites (1). 6/9 patients achieved stable disease lasting ≥ 16 weeks. Conclusions: The combination of cetuximab and pembrolizumab is well-tolerated in this study and can be administered at full dosages. Though hypomagnesemia appears prominent, no additional emergent AEs have been observed during or following the DLT period. The associated ongoing phase II study will enroll an additional 33 patients to assess the true efficacy of this regimen with dual primary endpoints of ORR and 6 month PFS. Clinical trial information: NCT02713373.


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