scholarly journals P05.02 A phase I/IIa dose escalation study evaluating the safety and efficacy of autologous CD34+ enriched hematopoietic progenitor cells genetically modified for human interferon-α2 in patients with GBM and an unmethylated MGMT promoter (TEM-GBM-001)

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii34-iii34
Author(s):  
B Gentner ◽  
F Ciceri ◽  
F DiMeco ◽  
F Legnani ◽  
M Eoli ◽  
...  
Keyword(s):  
Phase I ◽  
Poor Prognosis ◽  
Conditioning Regimen ◽  
Gene Promoter ◽  
Human Interferon ◽  
Interferon Α ◽  
Antitumor Effects ◽  
Dose Escalation Study ◽  
Mgmt Promoter

Abstract BACKGROUND Glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. Most patients with GBM & an unmethylated O-6-methylguanine-DNA methylase (MGMT) gene promoter, have a poor prognosis with approximately 20% of patients surviving to 2 years. Poor prognosis is likely related to a number of factors including a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) & microglia. A subset of tumor-infiltrating macrophages characterized by expression of the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis & are infrequently found in normal organs. Tie2 is significantly upregulated upon homing to tumors. Gene therapy technology has allowed TEMs to be used as carriers for the local and tumor restricted release of interferon-α (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Cell-based delivery of IFN into the TME by TEMs is expected to provide efficacy, taking advantage of pleiotrophic anti-tumor effects & avoiding tolerability issues associated with systemic IFN treatment. MATERIAL AND METHODS We are currently conducting a Phase I/IIa clinical study in Milan to evaluate this therapeutic approach (Temferon) in 21 patients with GBM & unmethylated MGMT promoter (EudraCT Number 2018- 001404-11). The study recruits & follows up patients at a specialist neurosurgical & neuro-oncology unit (INCB); administration of Temferon & hematological follow up takes place at a specialist hematology & bone marrow transplantation unit at OSR. Potentially eligible patients are identified immediately after first surgical resection of GBM once the MGMT promoter methylator status is known. Once screening procedures have been completed, harvesting of HSPCs occurs followed by 6 weeks of radiotherapy. Patients receive a non-myeloablative conditioning regimen consisting of BCNU & thiotepa. This is followed by administration of non-manipulated HSPCs and Temferon. In-patient monitoring occurs until hematological recovery. Thereafter, regular follow-up of patients occurs up to 2 years (+720 days) and patients will be invited to participate in a long term follow-up study lasting an additional 6 years. RESULTS In Part A of the study, 3 cohorts of 3 patients will receive escalating doses of Temferon. On completion of Part A, a single dose of Temferon will be selected to be studied in a further 12 patients in Part B. Criteria for study eligibility are the same for both Part A and Part B. In the event that GBM disease progression occurs, patients will be managed with second line therapies including second surgery, TMZ, BCNU, fotemustine or any other approved therapy for GBM. Patient recruitment for Part A is ongoing with the first dose of Temferon administered in July 2019.

scholarly journals ATIM-36. TEM-GBM-001 STUDY: AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2 & ADMINISTERED TO PATIENTS WITH GLIOBLASTOMA & AN UNMETHYLATED MGMT PROMOTER

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi9-vi9
Author(s):  
Gaetano Finocchiaro ◽  
Bernhard Gentner ◽  
Fabio Ciceri ◽  
Francesco DiMeco ◽  
Federico Legnani ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Gene Promoter ◽  
Human Interferon ◽  
Interferon Α ◽  
Antitumor Effects ◽  
Immune System Cell ◽  
Mgmt Promoter ◽  
The Status ◽  
Immunosuppressive Tumor Microenvironment ◽  
Ifn Treatment

Abstract BACKGROUND Most patients with GBM & an unmethylated O-6-methylguanine-DNA methylase (MGMT) gene promoter, have a poor prognosis with approximately 20% of patients surviving to 2 years. Poor prognosis is likely related to factors including a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) & microglia. A subset of tumor-infiltrating macrophages characterized by expression of the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis & are infrequently found in normal organs. Tie2 is significantly upregulated upon homing to tumors. Gene therapy technology has allowed TEMs to be used as carriers for the local and tumor restricted release of interferon-α (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Cell-based delivery of IFN into the TME by TEMs is expected to provide efficacy, taking advantage of pleiotropic anti-tumor effects & avoiding tolerability issues associated with systemic IFN treatment. We are currently conducting a Phase I/IIa clinical study in Milan (INCB & OSR) to evaluate this therapeutic approach (Temferon) in 21 patients with GBM & unmethylated MGMT promoter (EudraCT Number 2018-001404-11). Eligible patients are identified immediately after first surgical resection. After screening, harvesting of HSPCs occurs followed by 6 weeks of radiotherapy. Non-myeloablative conditioning consists of BCNU & thiotepa followed by administration of non-manipulated HSPCs and Temferon. RESULTS In Part A of the study, 3 cohorts of 3 patients will receive escalating doses of Temferon. After Part A, a single dose of Temferon will be studied in a further 12 patients (Part B). Criteria for study eligibility are the same for both Part A and Part B. Part A is ongoing with the first 2 patients recruited (June 2019) and Temferon is scheduled for administration. An update on the status and progress of the study will be provided.

scholarly journals CTIM-24. AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2, ARE WELL TOLERATED & RAPIDLY ENGRAFT IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (TEM-GBM_001 STUDY)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii38
Author(s):  
Gaetano Finocchiaro ◽  
Bernhard Gentner ◽  
Marica Eoli ◽  
Farina Francesca ◽  
Elena Anghileri ◽  
...  
Keyword(s):  
Disease Progression ◽  
Ex Vivo ◽  
Genetically Modified ◽  
Conditioning Regimen ◽  
Gene Promoter ◽  
Human Interferon ◽  
Open Label ◽  
Antitumor Effects ◽  
Open Label Phase ◽  
Interferon Α2

Abstract GBM with an unmethylated MGMT gene promoter is associated with very poor prognosis. A subset of tumor associated macrophages expressing the angiopoietin receptor Tie2 (TEMs) can be genetically modified for local & tumor restricted release of interferon-α2 (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Temferon consists of autologous HSPCs transduced ex-vivo with an LVV encoding an IFN gene & expression control sequences for TEMs. TEM-GBM is an open-label, Phase I/IIa study (Part A: 3x3x3 dose escalation; Part B: n=12), & Temferon (single dose) is given to patients with first diagnosis of GBM & unmethylated MGMT promoter. Part A 3rd cohort is ongoing & completes dosing in September 2020. Eight patients completed screening; one patient died (disease progression) before Temferon was administered. Six patients received Temferon (3 women, 3 men, mean age 52.3 years). Cohort 1 received Temferon 0.5x106 cells/kg & Cohort 2, 1x106 cells/kg. Neutropenia & thrombocytopenia occurred as expected following conditioning & hematologic recovery (HR) occurred median D+13. Transduced PBMCs were identified by vector copy number (VCN) on myeloid cells at HR & at later timepoints. In general, a dose-ordered increase in VCN was observed (mean VCN D+30 CD14+ Cohort 1: 0.094, cohort 2: 0.125); 1 patient in each cohort had low VCNs. VCN remained detectable up to recent follow up visits (≤ D+180). No dose-limiting toxicities have been reported. Four SAEs occurred in 3 patients who received Temferon (pneumonia, pulmonary embolism, febrile neutropenia, fatigue) but these events were not attributed to Temferon, resolved, & may have been related to the conditioning regimen (carmustine & thiotepa). Disease progression has been confirmed in 3 patients who received Temferon. These preliminary results indicate feasibility of engrafting a pre-determined fraction of Temferon cells in the bone marrow of GBM patients without, so far, causing dose-limiting toxicity.

Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 922-922 ◽  
Author(s):  
Mark Goodman ◽  
William I. Bensinger ◽  
Sergio Giralt ◽  
Donna Salzman ◽  
Katherine L. Ruffner ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Complete Response ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Red Marrow

Abstract Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented. Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months. Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials. Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis.

A phase I study of bevacizumab (B) with fluorouracil (F) and hydroxyurea (H) with concomitant radiotherapy (X) (B-FHX) for poor prognosis head and neck cancer (HNC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5530-5530 ◽  
Author(s):  
T. Y. Seiwert ◽  
D. J. Haraf ◽  
E. E. Cohen ◽  
K. Stenson ◽  
A. M. Mauer ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Poor Prognosis ◽  
High Risk Patient ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Tumor Bed ◽  
Grade 5 ◽  
Unclear Etiology ◽  
Ecog Ps

5530 Background: Increased VEGF levels are found in HNC. Preclinical data suggest synergistic antitumor activity of B with radiation and chemotherapy. We conducted a Phase I dose escalation study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of B, when added to infusional 5-FU, Hydroxyurea (HU), and daily radiotherapy administered every other week in patients (pts) with poor prognosis HNC. Methods: Eligible pts had recurrent, or newly diagnosed HNC with high risk of recurrence, ± metastatic disease requiring local control, ECOG PS ≤2, and life expectancy >12 weeks. Two week cycles were repeated 6–7 times (see table ). Results: 43 pts were treated (34 completed). DLT was reached at level 3 with 2 pts having gr 3 transaminase elevations and one pt gr 4 neutropenia. Treatment of 7 (6 evaluable) pts on level 4 resulted in one DLT (SMV thrombosis) and this dose level was chosen for expanded evaluation. In all level 4 pts (N = 27) gr 3 mucositis occured in 73.1% and gr 3 hand-foot syndrome in 15.4%. Additional gr 3 or worse toxicities in the expanded level 4 included: esophageal bleed (tumor bed, grade 5), stroke (grade 4), carotid rupture (3 wks post RT, grade 5), and neck ulceration with need for carotid stent (3 months post RT, grade 4). One sudden death of unclear etiology occurred. Median overall survival is 389 days. One/two year survival is 52.1/26%. Median survival for patients treated with re-irradiation for recurrent, non-metastatic HNC is 314 days; one/two year survival is 45.9/17.2%. With a median follow-up of 317 days 13 patients are still alive (12 are cancer free). Conclusions: B can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every 2 weeks. While B related toxicities are seen, there appears to be no major synergistic toxicity. Long term activity is observed in this very high risk patient population. A randomized phase II trial of FHX with or without B in a lower risk population is ongoing. [Table: see text] No significant financial relationships to disclose.

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.

Long-Term Efficacy of Dasatinib in Chronic-Phase CML: Results from the Phase I Trial (CA180002).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1026-1026 ◽  
Author(s):  
Jorge Cortes ◽  
Charles L. Sawyers ◽  
Hagop M. Kantarjian ◽  
Neil P. Shah ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase I ◽  
Median Duration ◽  
Chronic Phase ◽  
Interferon Α ◽  
First Year ◽  
Imatinib Resistance ◽  
Imatinib Resistant

Abstract Imatinib resistance in CML is frequently associated with BCR-ABL mutations. Such kinase domain mutations are emerging as a common mechanistic theme in cases of acquired resistance to kinase inhibitor therapy. Five-year follow-up from the IRIS trial indicates that the incidence of hematologic resistance to imatinib is 17% and >30% of patients have discontinued imatinib therapy on study. Preclinical studies reveal that dasatinib (SPRYCEL®), a novel BCR-ABL inhibitor, is 325-fold more potent than imatinib in inhibiting the kinase activity of BCR-ABL, as well as demonstrating activity against all imatinib-resistant BCR-ABL mutations tested to date, with the exception of T315I. Here we present an update of a Phase-I dose-escalation study, with enrollment between November 2003 and April 2005, of dasatinib in imatinib-resistant or -intolerant patients with CML or Ph+ ALL; this report focuses on the long-term follow-up of the 45 patients (56% male) with late chronic-phase disease. Dasatinib was administered at doses of 15–180 mg/day on a QD or BID schedule. Median duration of CML prior to entry was 8 years (range 1–17). Median age was 63 years (range 28–79). Prior therapy included interferon-α in 91% of patients and stem-cell transplantation in 4%; 62% had received prior imatinib doses >600 mg. With a minimum follow-up of 27 months, the rate of complete hematologic response (CHR) was 91% (41/45). Major cytogenetic responses (MCyR) were attained in 51% of patients (23/45), with complete CyR (CCyR) in 44% (20/45). The rates of CCyR for the QD and BID schedules were 45% (10/22) and 43% (10/23), respectively. The median duration of CHR and MCyR have not been reached with a median duration of treatment of 28 months. In a landmark analysis, the 36-month progression-free survival (PFS) rate was 87% and overall survival (OS) was 94% for patients who achieved a MCyR within the first year of dasatinib therapy. For patients who did not achieve a MCyR within the first year, the 36-month PFS figure was 28% and OS was 68%. These long-term data confirm the durability and depth of hematologic and cytogenetic response associated with dasatinib in patients who have failed treatment with imatinib. Evidence is also provided to substantiate that the significant response rates observed with dasatinib therapy in this population translate into prolonged progression-free and overall survival. Dasatinib therefore has the potential to positively impact on the natural history of CML.

A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases (ILM) from colorectal cancer (CRC).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 283-283
Author(s):  
Deepa Magge ◽  
Amer H Zureikat ◽  
David L. Bartlett ◽  
Matthew Peter Holtzman ◽  
Haroon Choudry ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Systemic Exposure ◽  
Fixed Dose ◽  
Dose Escalation Study ◽  
Total Platinum ◽  
Isolated Hepatic Perfusion ◽  
Prospective Phase ◽  
Grade 3

283 Background: IHP is a proven approach for regional delivery of chemotherapy in patients with unresectable ILM. This study sought to determine safety and MTD of administering 5FU in combination with fixed dose oxaliplatin via IHP. Methods: Prospective Phase I dose escalation with standard 3x3 dosing. Subjects with unresectable ILM from CRC scheduled to receive an HAI pump were eligible. IHP employed fixed dose oxaliplatin (previously established)with escalating doses of 5FU. 1 endpoint was to determine MTD for this combination. 2 endpoints were response to IHP alone, PFS, and OS for IHP + HAI-FUDR. Systemic and IHP plasma PK of 5FU, anabolites, total, and free platinum were determined by validated assays. Results: Between Aug 2007 - Mar 2011, 11 subjects were enrolled. All patients received at least one line of pre-IHP systemic chemotherapy. There were 4 Grade 3 SAE (36.3%) and no grade 4 events. 2 DLTs occurred in the second dose cohort of 300mg/m2. Dose escalation was terminated and 200mg/m2 5FU was determined to be the MTD. There was 1 DLT in the dose de-escalating phase of 200mg/m2. At first follow-up, 9 pts (82%) had a partial response, while 2 (18%) had stable disease. 64% of pts had a >50% decrease in CEA level. Actuarial 1 and 2 year survival was 100% and 75% respectively, with median follow-up of 23 mos. IHP exposures (AUC0-60min) were 10.9±4.5 µgPt·h/mL (platinum), 49.3±30.7 µg·h/mL 5FU (DL1) and 70.5±35.5 µg·h/mL 5FU (DL2). Free platinum represented 82±14% of total platinum. Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both total platinum (1.1±1.5%) and 5FU (0.09±0.10%). IHP exposure to metabolites relative to 5FU was 4.9±2.5% for FUrd and 0.23±0.14% for FdUrd, respectively. Conclusions: MTD for IHP with 5FU and oxaliplatin is 200 mg/m2 and 40mg/m2 respectively. Systemic exposure to the agents was minimal. The response and survival observed in this dose escalation study warrants assessment in a larger phase II trial. [Table: see text]

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.

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