Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9533-9533 ◽  
Author(s):  
Michael B. Atkins ◽  
John M. Kirkwood ◽  
Jedd D. Wolchok ◽  
Margaret K. Callahan ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Performance Status ◽  
Study Drug ◽  
Advanced Melanoma ◽  
Post Treatment ◽  
Dose Escalation Study ◽  
Term Survival

9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.

scholarly journals Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study

2018 ◽  
Vol 36 (4) ◽  
pp. 391-398 ◽  
Author(s):  
Margaret K. Callahan ◽  
Harriet Kluger ◽  
Michael A. Postow ◽  
Neil H. Segal ◽  
Alexander Lesokhin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Dose Escalation ◽  
Objective Response ◽  
Safety Data ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

scholarly journals DOP60 Vedolizumab treatment persistence and safety in an extended access program (XAP)

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S099-S100
Author(s):  
S Danese ◽  
K Subramanian ◽  
J Van Zyl ◽  
S Adsul ◽  
D Lindner ◽  
...  
Keyword(s):  
Data Analysis ◽  
Adverse Events ◽  
Dose Escalation ◽  
Open Label ◽  
Dose Escalation Study ◽  
Extended Access ◽  
Dosing Frequency ◽  
Access Program

Abstract Background Vedolizumab, a gut-selective, α 4β 7 integrin antagonist, has been established as an effective and safe treatment for patients with UC or CD in the GEMINI phase 3 program and long-term safety (LTS) study. An extended access program (XAP) was initiated to provide continued access to patients who were benefiting from vedolizumab in GEMINI LTS and to monitor safety. We now report persistence and safety results from a 2-year data analysis. Methods Vedolizumab XAP (NCT02743806) is a phase 3b/4 prospective, open-label, multinational interventional study. A rollover from GEMINI LTS (NCT00790933) to the XAP, patients reduced dosing frequency from vedolizumab 300 mg IV every 4 weeks (Q4W) to every 8 weeks (Q8W) or remained on vedolizumab 300 mg IV Q4W if medically indicated. This 2-year data analysis assessed persistence on Q8W dosing after dosing frequency reduction, need for escalation to Q4W dosing, incidence of relapse (defined as dose escalation, study withdrawal due to adverse event, loss of adequate benefit from vedolizumab, or increased corticosteroid [CS] or immunomodulator dose), and safety 2 years after rollover from GEMINI LTS. Results A total of 311 patients (142 UC, 169 CD) from GEMINI LTS enrolled in the XAP. Median (range) duration of exposure to vedolizumab prior to the XAP was 8.0 years (5.2–10.0) for patients with UC and 7.5 years (5.4–9.9) for patients with CD. Of patients with UC and CD, 93.0% and 84.6%, respectively, reduced dosing frequency to Q8W at XAP start, and 87.3% and 77.5%, respectively, remained on Q8W after 2 years. At baseline, 93.0% of all patients with UC and 88.2% of all patients with CD were in CS-free remission; patients who maintained Q4W dosing at baseline had lower CS-free remission rates (62.5% in UC and 69.2% in CD). Of patients who initiated Q8W dosing at enrolment in the XAP, 95% had no relapse for ≥6 months (97.0% UC, 93.7% CD; Table 1). Only 7.3% of patients required dose escalation to Q4W, and 11.6% experienced relapse during the 2-year follow-up. Times to dose escalation and relapse were similar in patients with UC and CD (Figures 1 and 2). At 2 years, 4 of 8 patients with UC and 4 of 12 patients with CD who required dose escalation to Q4W discontinued vedolizumab early due to loss of benefit or adverse events. Adverse events related to vedolizumab were infrequent; no new or serious events attributed to vedolizumab were reported. Conclusion High patient persistence on Q8W vedolizumab was observed in the first 2 years after reduction of dosing frequency in the XAP. Overall, there were low rates of Q4W dose escalation and CD or UC disease relapse. The safety profile was consistent with previous reports with no new signals observed.

scholarly journals Survival of Critically Ill Oncologic Patients Requiring Invasive Ventilatory Support: A Prospective Comparative Cohort Study With Nononcologic Patients

2019 ◽  
pp. 1-8
Author(s):  
Rene López ◽  
Suraj Rajesh Samtani ◽  
Jose Miguel Montes ◽  
Rodrigo Perez ◽  
Maria Jose Martin ◽  
...  
Keyword(s):  
Critically Ill ◽  
Performance Status ◽  
Chronic Health Evaluation ◽  
Health Evaluation ◽  
Ecog Performance Status ◽  
Term Survival ◽  
Mechanically Ventilated ◽  
Oncologic Patients

PURPOSE Cancer is in the process of changing to become a chronic disease; therefore, an increasing number of oncologic patients (OPs) are being admitted to intensive care units (ICUs) for supportive care of disease or therapy-related complications. We compare the short- and long-term outcomes of critically ill mechanically ventilated OPs with those of their nononcologic counterparts. PATIENTS AND METHODS We performed a prospective study of patients admitted to our ICU between October 2017 and February 2019. Demographic, physiologic, laboratory, clinical, and treatment data were obtained. The primary outcome was survival at 28 days and at the end of the follow-up period. Secondary outcomes were survival according to acute severity scoring (Acute Physiology and Chronic Health Evaluation II score), Eastern Cooperative Oncology Group (ECOG) performance status, and Charlson comorbidity index. RESULTS A total of 1,490 patients were admitted during the study period; 358 patients (24%) were OPs, and 100 of these OPs were supported with mechanical ventilation. Seventy-three percent of OPs had an ECOG performances status of 0 or 1, and 90% had solid tumors. Reason for admission to the ICU was postoperative admission in 44 patients and neutropenic infection in 10 patients. The follow-up period was 148 days (range, 42 to 363 days). Survival at 28 days was similar between OPs and nononcologic patients and associated with the Acute Physiology and Chronic Health Evaluation II score. However, long-term survival was lower in OPs compared with nononcologic patients (52% v 76%, respectively; P < .001) and associated with poor ECOG performance status. CONCLUSION Short-term survival of critically ill, mechanically ventilated OPs is similar to that of their nononcologic counterparts and is determined by the severity of the critical illness.

Total Lymphoid Irradiation and High-Dose Chemotherapy with Autologous Blood Stem-Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma: Excellent Disease Control and Long-Term Survival Rates

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2024-2024
Author(s):  
Ryan D. Gentzler ◽  
Andrew M. Evens ◽  
Alfred W. Rademaker ◽  
Bharat B Mittal ◽  
Adam M. Petrich ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Survival Rates ◽  
Standard Of Care ◽  
High Dose Chemotherapy ◽  
Salvage Chemotherapy ◽  
High Dose ◽  
Term Survival

Abstract Abstract 2024 Background: For patients with relapsed or refractory HL, salvage chemotherapy followed by aHSCT is the standard of care. Our group previously reported excellent clinical outcomes with accelerated hyperfractionated TLI followed by high-dose chemotherapy and aHSCT (Ann of Oncol. 16:679, 2007). This strategy has been adopted as the standard at our institution for eligible individuals and we now report long-term outcomes of patients previously reported on the phase I/II clinical trial in addition to those who were subsequently treated as standard of care. Patients and methods: Patients with biopsy confirmed relapsed/refractory classical HL who previously received no more than 20 Gy were eligible. Salvage chemotherapy was chosen by the patient's treating physician. All patients received accelerated hyperfractionated TLI prior to transplantation administered twice daily at 150 cGy, five days/week for 10 days. The morning dose was delivered to all nodal sites including the spleen, and the afternoon dose was delivered to all sites of previous and current disease. The goal was to treat uninvolved nodal sites and spleen to 1500 cGy and sites of current and previous disease to 3000 cGy. Conditioning chemotherapy consisted of high-dose carboplatin, cyclophosphamide, and etoposide. All patients received carboplatin 450 mg/m2 by continuous intravenous infusion (CIV) on days –6 to –4 (total dose = 1350 mg/m2) and cyclophosphamide 60 mg/kg/day over 1 h on days –3 and –2 (total dose = 120 mg/kg). Patients on the phase I portion of the trial received escalating doses of etoposide by CIV from days –6 to –4. Initial dosing levels were 400 mg/m2/day, 450 mg/m2/day, 500 mg/m2/day, 600 mg/m2/day and 700 mg/m2/day. Those treated on the phase II portion of the clinical trial or subsequent to the closing of the trial were treated with etoposide 700 mg/m2/day for a total of 2100 mg/m2. Results: 52 patients with relapsed/refractory HL at Northwestern University were treated with TLI and aHSCT from 1993 to January 2011. One patient was lost to follow-up immediately post-transplant. 51 patients were included in this analysis and had a median follow-up of 47 months (range: 0.07–204 months). Thirty patients were treated on a previously reported prospective phase I/II clinical trial. Most patients had nodular sclerosis histology (n=39, 76%) and more than half had primary induction failure (PIF; n=29). Among patients who achieved a CR with induction, 62% relapsed within one year. The most common salvage regimens were ESHAP and ICE chemotherapy and most had received two lines of chemotherapy prior to aHSCT. Only 21 patients (41%) achieved a complete response (CR) with salvage therapy and in most cases (n=31, 61%), response was determined by functional imaging prior to aHSCT. The 10-year PFS and OS for all patients were 56% and 54%, respectively. Ten-year PFS and OS for patients with PIF was 53%, compared with 63% and 59%, respectively, for those with relapsed disease (p=0.13 and p=0.20, respectively). Patients who had incomplete responses to salvage therapy had a 10-year PFS and OS of 41% and 39%, respectively, compared to 76% and 81%, respectively, for those who achieved a CR (p=0.1 and p=0.056, respectively). Treatment-related mortality within the first 100 days was observed in one patient. Five patients (10%) developed secondary malignancies; three developed MDS (one who had received MOPP induction died with MDS; one had relapsed HL post-aHSCT and died of AML and one is alive with MDS 3+ yrs post-diagnosis). There was one case each of T-cell lymphoma (7 months post-aHSCT) and melanoma. Conclusions: Sequential TLI/chemotherapy conditioning for relapsed/refractory HL for patients with limited or no prior radiotherapy continues to be associated with excellent disease control and long-term survival rates including high-risk populations such as PIF and chemotherapy-resistant disease. Disclosures: No relevant conflicts of interest to declare.

Phase I dose escalation study of TG02 in patients with advanced hematologic malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6577-6577 ◽  
Author(s):  
Gail J. Roboz ◽  
Hanna Jean Khoury ◽  
Jamile M. Shammo ◽  
Mary Syto ◽  
Francis Burrows ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Intensive Therapy ◽  
Study Drug ◽  
Underlying Disease ◽  
Median Number ◽  
Open Label ◽  
Dose Escalation Study ◽  
Multikinase Inhibitor ◽  
Dose Levels

6577 Background: TG02 is a novel multikinase inhibitor with a unique spectrum of activity, targeting both the cell cycle regulatory cyclin-dependent kinases (CDKs) 1 and 2 and the transcriptional regulators CDKs 7 and 9. TG02 also inhibits the emerging oncogenic MAPK ERK5 and the DNA damage response mediator CDK5. TG02 kills primary blasts from a variety of hematologic cancers and is curative in the MV4-11 model of FLT3-mutant AML. Methods: This is a first-in-man,single arm, open label, phase I dose escalation trial. The primary endpoints are dose-limiting toxicity (DLT), maximally tolerated dose (MTD ) and recommended phase 2 dose (RP2D). Patients (pts) ≥ 18 years with advanced hematological malignancies or newly diagnosed AML pts ≥ 65 years unfit for intensive therapy were enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) schedules. Pts had acceptable organ function and ECOG PS 1-2. Definition of DLT was G3-4 AST or ALT ≥7 days, G4 AST or ALT, G4 hyperbilirubinemia, any other NCI CTC G3-4 events not due to underlying disease. Dose levels on arm A were 10mg to 70mg and 15mg-150 mg on arm B. Results: Forty-five pts have received at least one dose of study drug. Median age was 66 years (range, 37-87) and 80% were ECOG 0-1. Disease types enrolled included: AML (80%), high-risk MDS (22%), and CML-BC (3%). The median number of previous regimens was 3 (range, 1-12). The MTD on arm A was defined at 50 mg daily based on 2 DLTs at the 70mg dose level (G4 hyperbilirubinemia, G4 fatigue). Enrollment to arm B has competed dose levels 15 (N=3), 30 (N=3), 50 (N=3), 70 (N=3), 100mg (N=3), and enrollment at 150mg is ongoing without DLT to date. Common drug related adverse events were nausea (42%), vomiting (23%), fatigue (18%), decreased appetite (15%), constipation and diarrhea (13% each). Preliminary PK demonstrated dose proportional increases in exposure and a T1/2 , supporting once daily dosing. Conclusions: The MTD for TG02 has been determined for the daily schedule at 50mg. Enrollment continues on the intermittent schedule. Schedules of every other day and week on/week off dosing will also be evaluated.

Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9028-9028 ◽  
Author(s):  
Reinhard Dummer ◽  
Caroline Robert ◽  
Marta Nyakas ◽  
Grant A. McArthur ◽  
Ragini Reiney Kudchadkar ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Braf Inhibitor ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Pretreated Patients ◽  
Initial Results

9028 Background: LGX818, a potent and selective BRAF inhibitor (BRAFi) being investigated in BRAF V600 mutant melanoma, has unique biochemical properties with a dissociation half-time > 10 times longer than other BRAF inhibitors. Methods: A phase I trial of LGX818 administered orally once (qd) or twice (bid) daily in BRAF V600 tumors was initiated to define the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and to assess pharmacokinetics and clinical activity in BRAFi–naive or pretreated patients with BRAF V600 mutant advanced melanoma. Baseline assessment of biomarkers from MAPK/PI3K pathways and pharmacodynamics were also evaluated. Results: Fifty-four patients have been enrolled in the dose-escalation phase (dose levels [DLs], 50-700 mg qd [n=42] and 75-150 mg bid [n=12]). LGX818 plasma concentrations increased proportionally by dose with a mean t1/2 of 4 hours and steady state in ≈ 15 days. The MTD/RP2D (450 mg qd) was well tolerated. Seven patients had a dose limiting toxicity (DLT): 5 at qd (1 each with hand-foot skin reaction [HFSR], foot pain, fatigue, diarrhea/rash, insomnia/asthenia) and 2 at bid (1 facial paresis/confusion, 1 musculoskeletal pain/neuralgia). All DLTs were grade 3 and reversible. The most common adverse events (≥ 20%) suspected to be treatment related were cutaneous (rash, dry skin, HFSR, pruritus, keratosis pilaris, alopecia), pain in extremity, arthralgia, and fatigue. Squamous cell carcinoma was observed in 2 patients (1 naive and 1 pretreated). As of 30 Sept 2012, the preliminary efficacy (all DLs) in patients with at least 1 postbaseline tumor assessment was 16 partial responses [PRs] (67%; 12 confirmed) out of 24 BRAFi–naive patients and 2 PRs (8.3%; 1 confirmed) among 24 BRAFi–pretreated patients. Responses were seen at all DLs from 50 to 550 mg qd. Updated safety and efficacy including time to event endpoints will be reported. Conclusions: Initial results from this study identified the MTD/RP2D as 450 mg/day and provided an early sign of promising activity in advanced melanoma. Expansion cohorts are ongoing in BRAFi–naive and BRAFi–pretreated melanoma and colorectal cancer. Clinical trial information: NCT01436656.

A phase I dose escalation study of PCUR-101 in men with metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16517-e16517 ◽  
Author(s):  
Christos Kyriakopoulos ◽  
Channing Judith Paller ◽  
Ajit Verma ◽  
Karim Kader ◽  
Jeff Kittrelle ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Human Study ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Drug Formulation ◽  
Clinical Activity ◽  
Second Phase ◽  
Castration Resistant Prostate Cancer ◽  
Dose Escalation Study

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.

Long-term survival from pembrolizumab (pembro) completion and pembro retreatment: Phase III KEYNOTE-006 in advanced melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10013-10013 ◽  
Author(s):  
Georgina V. Long ◽  
Jacob Schachter ◽  
Ana Arance ◽  
Jean-Jacques Grob ◽  
Laurent Mortier ◽  
...  
Keyword(s):  
Clinical Care ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Term Survival ◽  
Long Term Survival ◽  
Prior Therapy ◽  
Additional Clinical Benefit ◽  
Ecog Ps

10013 Background: 5-year follow-up of the phase 3 KEYNOTE-006 study (NCT01866319) showed pembro improved OS vs ipilimumab (ipi) in patients (pts) with advanced melanoma. 3-y OS rate from pembro completion for pts who completed 2 y of pembro was 93.8%. Results with 8 mo of additional follow-up are presented to inform clinical care. Methods: Eligible pts with ipi-naive advanced melanoma, ≤1 prior therapy for BRAF-mutant disease, and ECOG PS 0 or 1 were randomized to pembro 10 mg/kg Q2W or Q3W for ≤2 y or ipi 3 mg/kg Q3W for 4 doses. Pts discontinuing pembro with CR, PR, or SD after ≥94 weeks were considered pts with 2-y pembro. Pts who stopped pembro with SD, PR or CR could receive ≤12 mo of additional pembro (2nd course) upon disease progression if still eligible. ORR was assessed per immune-related response criteria by investigator review. OS was estimated using the Kaplan-Meier method. Pembro arm data were pooled. Post hoc ITT efficacy analyses are shown. Results: Median follow-up from randomization to data cutoff (Jul 31, 2019) was 66.7 mo in the pembro and 66.9 mo in the ipi arms. OS outcomes are shown in Table. For the 103 pts with 2-y pembro (30 CR, 63 PR, 10 SD), median follow-up from completion was 42.9 mo (95% CI, 39.9-46.3).Median DOR was not reached. 36-mo OS from pembro completion was 100% (95% CI, 100.0-100.0) for pts with CR, 94.8% (95% CI, 84.7-98.3) for pts with PR, and 66.7% (95% CI, 28.2-87.8) for pts with SD. 15 pts received 2nd-course pembro; BOR in 1st course was 6 CR, 6 PR, and 3 SD. Median time from end of 1st course to start of 2ndcourse was 24.5 mo (range, 4.9-41.4). Median follow-up in pts who received 2nd-course pembro was 25.3 mo (range, 3.5-39.4). Median duration of 2nd-course pembro was 8.3 mo (range, 1.4-12.6). BOR on 2ndcourse was 3 CR, 5 PR (ongoing responses, 7 pts), 3 SD (ongoing, 2 pts), and 2 PD (1 death); 2 pts pending. Conclusions: Pembro improves the long-term survival vs ipi in pts with advanced melanoma, with all pts who completed therapy in CR still alive at 5 years. Retreatment with pembro at progression in pts who stopped at SD or better can provide additional clinical benefit in a majority of pts. Clinical trial information: NCT01866319. [Table: see text]

Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 186-186
Author(s):  
Karl Zhou ◽  
Phoebe Zhang ◽  
Youzhi Tong ◽  
Liandong Ma
Keyword(s):  
Phase I ◽  
Clinical Outcomes ◽  
Dose Escalation ◽  
Tumor Biology ◽  
Study Drug ◽  
Resistance Mechanisms ◽  
Development Programs ◽  
Dose Escalation Study ◽  
Biomarker Analysis ◽  
Monitoring Treatment

186 Background: AR blockade is an important treatment option for mCRPC in clinic and GT0918 is a new chemical entity of AR blocker in 2nd generation. A phase I dose escalation study was planned in pts with mCRPC progressed on multiple lines of SoC and experimental therapies. Daily oral administration of GT0918 has shown better clinical outcomes in 400mg and 500mg cohorts with no comprised toxicities. To study the tumor biology in response to study drug in clinical setting, CTC and cfDNA/RNA based biomarkers were explored. Methods: Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw. Blood samples were collected at baseline, on study drug every 8 wks during the trial and pts with ≥ 3 blood test samples were qualified for various assays for CTCs and cfDNA/RNA via EPIC and PredicinePlus platforms. Results: Total 40 pts were orally administrated GT0918 with dose increasing 50, 100, 200, 300, 400, 500 and 600 mg daily and shown well tolerated with mild to moderate toxicities. Pts received GT0918 over 16 weeks were run biomarkers in Predicine and/or Epic platforms. ctDNA/RNA based variants and CTCs are all detectable in selected pts samples. AR splicing variants (AR-V3 and AR-V7), AR hotspot mutations (W742C, T878A and S889G) and amplifications were detected and shown interesting trends with the clinical outcomes. Both exploratory biomarkers and CTCs suggested higher doses of GT0918 resulted in better clinical outcomes. Conclusions: This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs. More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. Clinical trial information: NCT02826772. [Table: see text]

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