Cohort 1 results of a phase I study of autolytic immunotherapy of metastatic neuroendocrine neoplasms using intralesional rose bengal disodium.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16694-e16694
Author(s):  
Mark McGregor ◽  
Timothy Jay Price ◽  
Gabby Cehic ◽  
Ian D. Kirkwood ◽  
Ruben Sebben ◽  
...  
Keyword(s):  
Disease Control ◽  
Rose Bengal ◽  
Treatment Cycle ◽  
Phase 1 ◽  
Systemic Disease ◽  
Objective Response ◽  
Hepatic Metastases ◽  
Hepatic Lesion ◽  
Neuroendocrine Neoplasms ◽  
Contrast Enhanced Ct

e16694 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed, especially when available options have been exhausted. Intralesional (IL) rose bengal disodium (PV-10), an autolytic immunotherapy under development for solid tumors, is being investigated as a potential option for treatment-refractory patients (pts) with hepatic metastases. Methods: This phase 1 study is evaluating the safety, tolerability and objective response resulting from percutaneous administration of PV-10 in 12 pts with progressive mNEN refractory to SSA and PPRT; pts must have at least one injectable hepatic lesion (1.0-3.9 cm in longest diameter) not amenable to resection or other potentially curative therapy. In Cohort 1 (n = 6) pts received PV-10 to a single hepatic lesion per treatment cycle, and could receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. The primary endpoint is safety. Secondary endpoints include objective response rate assessed by independent review of contrast enhanced CT and by 68Ga-DOTATATE PET. Results: Cohort 1 has fully enrolled, with 4 of 6 pts male, median age 65 yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1. NET grade: Gd1 = 5, Gd2 = 1. All pts had progressed on prior SSA and PRRT. Median baseline CgA was 645 (range 30-2819). One pt received 4 PV-10 treatment cycles, 1 received 2 cycles, and 4 received a single cycle. Toxicity was acceptable, including transient pain post procedure, carcinoid flare and nausea. A partial response of injected lesions was observed in 50% of pts (injected lesion progression in 1 pt), with an overall response of stable disease achieved in 84% of pts by RECIST 1.1 (progressive disease in 1 pt). Progression free survival (PFS) was not reached by CT (range 2.4-25.3+ months), and was 6.1 months by PET. Median overall survival (OS) was ≥22.5 months, with three subjects alive at the data cut-off of Jan 2020 (range 18.1-33.8 months). Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local response of injected tumors and prolonged systemic disease control in some pts. Enrolment to Cohort 2 is nearing completion where an additional 6 pts may receive injection of multiple lesions per treatment cycle. Clinical trial information: NCT00986661 .

Phase I study of autolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4115-4115
Author(s):  
Timothy Jay Price ◽  
Gabby Cehic ◽  
Eric Andrew Wachter ◽  
Ian D. Kirkwood ◽  
Jessica Reid ◽  
...  
Keyword(s):  
Disease Control ◽  
Rose Bengal ◽  
Treatment Cycle ◽  
Phase 1 ◽  
Systemic Disease ◽  
Symptom Control ◽  
Objective Response ◽  
Neuroendocrine Neoplasms ◽  
Contrast Enhanced Ct ◽  
Patient Reported

4115 Background: Metastatic neuroendocrine neoplasms (mNEN) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, systemic somatostatin analogues (SSA), and systemic peptide receptor radionuclide therapy (PRRT). Additional options are needed; we have explored intralesional (IL) rose bengal disodium (PV-10), an investigational autolytic immunotherapy that can yield immunogenic cell death and disease-specific functional adaptive immunity. Methods: This phase 1 study evaluated safety, tolerability and impact on symptoms and biochemical markers resulting from IL PV-10 administered percutaneously to hepatic lesions in patients (pts) with progressive mNEN not amenable to resection or other potentially curative therapy. Eligible lesion(s) were 1.0 - 3.9 cm in longest diameter with amount of PV-10 administered proportional to size. Cohort 1 (n = 6 pts) received PV-10 to a single lesion per treatment cycle; Cohort 2 (n = 6) could receive injection to multiple lesions per treatment cycle. Pts could receive further PV-10 ≥6 weeks after prior injection. The primary endpoint was safety. Secondary endpoints included objective response rate (ORR) assessed by contrast enhanced CT (RECIST 1.1) and 68Ga-DOTATATE PET, biochemical response (CgA) and patient-reported outcome (EORTC QLQ-C30 and GI.NET21 QOL instruments). Results: Twelve pts were enrolled, 50% male, median age 66 yrs (range 47-79). Primary sites: 7 small bowel, 2 pancreas, 1 caecal, 2 unknown; grade: Gd1 = 5, Gd2 = 7. All pts had received SSA and PRRT as part of previous therapy and all had symptomatic, progressive disease. Median CgA was 1585 (range 35-10370). One lesion was injected per cycle for all 12 pts; none were suitable for multiple injections. One pt received 4 sequential PV-10 treatment cycles, 3 received 2 cycles, and 8 received 1 cycle. Toxicity was consistent with experience in other hepatic malignancies: post-procedure pain was reported by most pts; grade 3 photosensitivity reaction occurred in 1 pt; and grade 1 elevation of hepatic enzymes attributed to PV-10 occurred in 2 pts, resolving by day 7. Additionally, carcinoid flare occurred in 1 pt. ORR of injected lesions was 42%; patient-level disease control was 84%. Estimated PFS was 9.2 months; median OS was 22.5 months. CgA remained stable in 10 pts and upregulation of NK and activated CD4+ T lymphocytes was observed post-injection. QOL data at months 1 and 3 showed stable or improved carcinoid symptoms and global health status in 9 pts. Conclusions: PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease and symptom control in a heavily pre-treated population. Multiple cycles were delivered safely in suitable patients. Adaptive immune upregulation is consistent with other solid tumors and supports potential systemic benefit. Clinical trial information: NCT02693067.

A phase I study of oncolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium: Cohort 1 results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4102-4102 ◽  
Author(s):  
Timothy Jay Price ◽  
Gabby Cehic ◽  
Eric Andrew Wachter ◽  
Ian Kirkwood ◽  
Rubin Sebbon ◽  
...  
Keyword(s):  
Disease Control ◽  
Rose Bengal ◽  
Treatment Cycle ◽  
Systemic Disease ◽  
Objective Response ◽  
Neuroendocrine Neoplasms ◽  
Contrast Enhanced Ct ◽  
Patient Reported ◽  
Oncolytic Immunotherapy ◽  
Hepatic Lesions

4102 Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed and one such option is hepatic intralesional (IL) rose bengal disodium (PV-10), an oncolytic immunotherapy under development for solid tumours. Methods: This phase 1 study is evaluating the safety, tolerability and reduction of biochemical markers and symptoms resulting from percutaneous administration of PV-10 in 12 subjects with progressive mNEN with hepatic lesions not amenable to resection or other potentially curative therapy. Target lesion(s) must be 1.0 - 3.9 cm in longest diameter. In Cohort 1 (n = 6) subjects receive PV-10 to a single hepatic lesion per treatment cycle, and can receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. Cohort 2 (n = 6) subjects may receive injection of multiple lesions per treatment cycle. The primary endpoint is safety. Secondary endpoints include objective response rate (ORR) assessed by contrast enhanced CT and 68Ga-DOTATATE PET, biochemical response (CgA) and patient-reported outcome (EORTC QLQ-C30 and GI.NET21). Results: Cohort 1 has fully enrolled, with 4 of 6 subjects male, median age 65yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1; grade: Gd1 = 5, Gd2 = 1. All patients received prior SSA and PRRT. Median CgA was 645 (range 30-2819). To date 1 subject has received 4 PV-10 treatment cycles, 1 has received 2 cycles, and 4 have received a single cycle. Toxicity has been acceptable, including pain post procedure, carcinoid flare and nausea. LFT’s have remained stable. Overall QOL score was stable for 5 of 6 subjects. ORR in injected lesions is 50% (progression in 1 subject), with overall disease control of 84%. CgA response: 5 stable, 1 progression. One subject with “carcinoid pellagra” had rash resolution. Response follow-up is ongoing and additional efficacy and functional data will be presented. Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease control. Enrolment to Cohort 2 is underway. Clinical trial information: NCT02693067.

Chemoablation of melanoma with intralesional rose bengal (PV-10)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9060-9060
Author(s):  
S. S. Agarwala ◽  
J. Thompson ◽  
M. Smithers ◽  
M. Ross ◽  
B. Coventry ◽  
...  
Keyword(s):  
Disease Control ◽  
Rose Bengal ◽  
Phase 1 ◽  
Skin Flap ◽  
Objective Response ◽  
Safety Data ◽  
Stage Iii ◽  
Bystander Response ◽  
The Usa ◽  
Grade 3

9060 Background: Intralesional rose bengal (PV-10, a sterile 10% solution in saline) can elicit selective ablation of solid tumors and an apparent bystander response in untreated lesions. In phase 1 testing in 20 subjects with AJCC Stage III (19 subjects) or IV (1 subject) melanoma, a single injection of PV-10 into 1–20 lesions led to durable objective response (OR) at 12–24 weeks in 40% of subjects (20% CR + 20% PR by modified RECIST) and locoregional disease control (CR + PR + SD) in 75% of subjects. Untreated bystander lesions achieved an OR in 15% of subjects, and all subjects with an OR of their injected lesions achieved disease control of their bystander lesions. PV-10 was well tolerated, with only one Grade 3 adverse event (photosensitivity reaction). The most common AEs were transient pain at the treatment site (75% of subjects), followed by local inflammation or infection (25%). Methods: Expanded phase 2 testing commenced in late 2007 in up to 80 subjects with measurable Stage III or IV melanoma. After an initial treatment of 1–20 cutaneous, subcutaneous or nodal lesions, new or incompletely responsive lesions can be retreated at weeks 8, 12 or 16, with follow-up to 52 weeks. An additional 1–2 lesions, including visceral lesions, remain untreated for assessment of bystander response. Seven centers in Australia and the USA are enrolling subjects, with completion of enrolment expected by mid-2009. A modified Fleming design allows interim assessment of safety and OR at weeks 4 and 24, respectively, after treatment of the 20th and 40th subjects. The primary end-point is OR of injected lesions in the intent-to-treat population; secondary endpoints include OR of bystander lesions and PFS. Results: Interim safety data for the first 40 subjects treated is comparable to phase 1, with transient mild to moderate locoregional pain, vesicles or edema most common; Grade 3 AEs have been rare (1 case each of vesicles and skin flap necrosis), with no Grade 4 or 5 AEs attributed to PV-10. Interim efficacy for the first 20 subjects is also comparable to that of phase 1 (15% CR + 15% PR); efficacy data for the first 40 subjects will be presented at the meeting. Conclusions: The safety and efficacy profile of intralesional therapy with PV-10 compares favorably with available therapeutic options for this patient population. No significant financial relationships to disclose.

scholarly journals TRLS-06. PHASE 1 EXPANSION STUDY OF IRINOTECAN LIPOSOME INJECTION (nal-IRI) IN PATIENTS WITH METASTATIC BREAST CANCER (mBC): FINDINGS FROM THE COHORT WITH ACTIVE BRAIN METASTASIS (BM)

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i9-i9 ◽  
Author(s):  
Carey Anders ◽  
Pamela Munster ◽  
Donald Northfelt ◽  
Hyo Sook Han ◽  
Cynthia Ma ◽  
...  
Keyword(s):  
Disease Control ◽  
Phase 1 ◽  
Objective Response ◽  
Metastatic Breast ◽  
Median Number ◽  
Cns Metastases ◽  
Cns Disease ◽  
Topoisomerase 1 ◽  
Metastatic Setting ◽  
Heavily Pretreated

Abstract BACKGROUND: nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor). Preclinical data show that nal-IRI accumulates in BMs and prolongs survival in animal models of BM. Findings from a phase 1 expansion study (NCT01770353), evaluating patients with mBC and active BM, are reported. METHODS: This phase 1 expansion study enrolled patients with mBC who received multiple prior lines of cytotoxic therapy in the metastatic setting, including one cohort with mBC and active BM, defined as radiographic evidence of new or progressive central nervous system (CNS) metastases after radiation therapy with ≥1 lesion of ≥1 cm in the longest dimension on gadolinium-enhanced magnetic resonance imaging. Patients received nal-IRI 50 mg/m2 (free-base equivalent; FBE) every two weeks (q2w) as an intravenous infusion over 90 minutes, escalating to 70 mg/m2 FBE q2w, if tolerated. RECIST v1.1 and modified RECIST criteria were used to assses non-CNS and CNS disease, respectively. RESULTS: In total, 30 patients were enrolled (10 with active BM). Median age was 53 years (range 29–70 years) and median number of prior cytotoxic anti-cancer regimens was 3 (range 0–6); 29 patients received ≥1 dose of nal-IRI 50 mg/m2 FBE. Overall, nal-IRI monotherapy appeared to be well tolerated, and achieved ≥30% objective response rates for both CNS and non-CNS disease. Among the 10 patients with active BM, 6 achieved CNS disease control (3 partial responses [PRs] and 3 stable disease [SD]), including one patient with durable CNS SD and non-CNS PR for 2 years. Among 7 patients with serial evaluation of CNS metastases posttreatment, 6 patients achieved a reduction in target CNS lesions compared with baseline. CONCLUSION: Treatment with nal-IRI resulted in CNS disease control among 6 of 10 heavily pretreated patients with mBC and active BM. Further exploration of nal-IRI in patients with mBC and active BM is warranted.

scholarly journals Stereotactic Ablative Radiotherapy for the Management of Liver Metastases from Neuroendocrine Neoplasms: A Preliminary Study

2021 ◽  
Author(s):  
John Monte Hudson ◽  
Hans Tse-Kan Chung ◽  
William Chu ◽  
Amandeep Taggar ◽  
Laura Ellen Davis ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Local Control ◽  
Systemic Disease ◽  
Objective Response ◽  
Progression Free Survival ◽  
Late Toxicity ◽  
Response To Treatment ◽  
Neuroendocrine Neoplasms ◽  
Stereotactic Ablative Radiotherapy

Introduction: Liver metastases are common in patients with neuroendocrine neoplasms. The role of stereotactic ablative radiotherapy (SABR) is not well understood in this population. Objective: To evaluate the safety and efficacy of SABR in treating well-differentiated neuroendocrine liver metastases (WD-NELM). Methods: A retrospective review of patients with WD-NELM treated with SABR between January 2015-July 2019. Demographic, treatment and clinical/radiographic follow-up data were abstracted. RECIST 1.1 criteria were applied to each individual target to evaluate the response to treatment. Local control (LC) and progression free survival (PFS) were determined using Kaplan-Meier methodology. Toxicity was reported according to CTCAE v5.0. Results: Twenty-five patients with a total of 53 liver metastases treated with SABR were identified. Most patients (68%) had midgut tumors, were Grade II (80%) and had high volume intrahepatic and/or extrahepatic disease (76%). Median number of liver metastases treated was 2 with a median size of 2.5 cm. Median radiation dose delivered was 50Gy/5 fractions. Median follow-up was 14 months; 24 of the 25 patients were alive at time of analysis. The objective response rate (ORR) was 32%, with improvement or stability in 96% of lesions treated. The median time to best response was 9 months. The 1-year LC and PFS were 92% and 44% respectively. No Grade III/IV acute or late toxicity was identified. Conclusions: Liver SABR is a safe and promising means of providing local control for WD-NELM. This treatment modality should be evaluated in select patients in concert with strategies to manage systemic disease.

CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRASG12C, in patients with advanced colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4018-4018 ◽  
Author(s):  
Marwan Fakih ◽  
Jayesh Desai ◽  
Yasutoshi Kuboki ◽  
John H. Strickler ◽  
Timothy Jay Price ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Small Molecule ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Bound State ◽  
Molecular Testing ◽  
Duration Of Response ◽  
Heavily Pretreated

4018 Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation is associated with poor prognosis in colorectal cancer (CRC). AMG 510 is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C by locking it in the inactive guanosine diphosphate-bound state. In a previous interim analysis of the phase 1, first-in-human trial of AMG 510, we observed a favorable safety profile and preliminary antitumor activity in patients (pts) with advanced solid tumors harboring KRAS p.G12C. Here, we present updated data in pts with CRC. Methods: Key inclusion criteria were KRAS p.G12C mutation identified through molecular testing, measurable disease, and progression on standard therapy. Primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), as assessed per RECIST 1.1, and overall survival (OS). Oral daily doses of 180, 360, 720, and 960mg were tested in the dose escalation phase, and 960mg dose was selected for the expansion phase. Results: As of Jan 8, 2020, 42 pts with CRC (21 female [50%], median age: 57.5 years [range: 33–82]) were enrolled and dosed (25 on 960mg). All pts received prior systemic therapies; 19 pts (45.2%) received > 3 prior lines. Median follow-up was 7.9 months (mos) (range: 4.2–15.9). 13 pts (31.0%) died, and 8 pts (19.0%) remained on treatment (tx). 22 (52.4%) and 8 (19.0%) pts had remained on tx for more than 3 and 6 months, respectively. Progressive disease was the most common reason for tx discontinuation. 20 pts (47.6%) had tx-related adverse events (TRAEs): 18 (42.9%) had grade 2 or lower TRAEs; 2 (4.8%) had grade 3 TRAEs, which were diarrhea (2.4%) and anemia (2.4%). There were no dose-limiting toxicities, fatal TRAEs, or TRAEs leading to tx discontinuation. Overall, ORR and DCR were 7.1% (3/42) and 76.2% (32/42), respectively. At 960mg, ORR and DCR were 12.0% (3/25) and 80.0% (20/25). 3 pts with PR had duration of response of 1.5, 4.2, and 4.3 months, respectively, and their responses were still ongoing at data cutoff. In all pts treated with all doses, median duration of stable disease was 4.2 mos (range: 2.5[+]–11.0). PFS/OS will be reported. Conclusions: In pts with heavily pretreated KRAS p.G12C mutant CRC, AMG 510 monotherapy was well tolerated, with the majority of pts achieving disease control. Study is ongoing. Clinical trial information: NCT03600883 .

Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11003-11003 ◽  
Author(s):  
Silvia Stacchiotti ◽  
Patrick Schoffski ◽  
Robin Jones ◽  
Mark Agulnik ◽  
Victor Manuel Villalobos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Disease Control ◽  
Tumor Regression ◽  
Phase 1 ◽  
Epithelioid Sarcoma ◽  
Objective Response ◽  
Locally Advanced ◽  
Grade 3 ◽  
Favorable Safety

11003 Background: ES is a rare soft tissue sarcoma that metastasizes in approximately 30% to 50% of cases. More than 90% of ES tumors lack expression of INI1, an important component of epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2, to become an oncogenic driver in tumor cells. Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials. Methods: Data from a phase 2 open-label, multicenter trial of pts with locally advanced or metastatic ES are reported. Efficacy was assessed with primary and secondary endpoints including objective response rate (ORR) by RECIST 1.1, disease control rate (DCR; objective confirmed response of any duration or stable disease [SD] lasting ≥32 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS); safety and tolerability were also evaluated. Results: As of September 17, 2018, 62 INI1-negative ES pts were enrolled and treated with tazemetostat 800 mg BID. The median number of prior lines of therapy was 1 (range: 0-9). There were 9/62 (15%) confirmed partial responses (PRs) with an ORR of 15% and DCR of 26%. The DOR ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median OS of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 pts. Tazemetostat was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild to moderate with the most commonly reported adverse events (AEs; ≥10% incidence) regardless of attribution being fatigue (24/62; 39%), nausea (22/62; 35%), and cancer pain (20/62; 32%). Any treatment-related TEAEs of grade ≥3 were reported in 10/62 (16%) pts. TEAEs grade ≥3 reported in ≥2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat achieved disease control in 26% of pts with advanced ES who entered this study. Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety with few pts with treatment-related AEs grade ≥3. Clinical trial information: NCT02601950.

Intra-Arterial Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor Liver Metastases

2019 ◽  
Vol 03 (01) ◽  
pp. 081-090 ◽  
Author(s):  
Sander Ebbers ◽  
Maarten Barentsz ◽  
Arthur Braat ◽  
Marnix Lam
Keyword(s):  
Liver Metastases ◽  
Radionuclide Therapy ◽  
Liver Tumors ◽  
Objective Response ◽  
Hepatic Metastases ◽  
Peptide Receptor Radionuclide Therapy ◽  
Neuroendocrine Neoplasms ◽  
Original Research ◽  
Treatment Schedule ◽  
Peptide Receptor

Purpose Currently, peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-DOTATATE is used in patients with progressive neuroendocrine neoplasms (NEN) as salvage therapy. The standard treatment schedule consists of multiple cycles of intravenous (IV) administration. However, patients with liver metastases suffer from reduced tumor targeting and worse response and survival. This review provides an overview of the available evidence on the intra-arterial (IA) administration of radionuclide-labeled somatostatin analogues. Methods Databases of PubMed and Embase were searched systematically in May 2018 for studies that addressed IA PRRT. Included studies were original research publications focusing on absorbed tumor dose or tumor response after IA administration of PRRT for NEN. Publications on combined PRRT with other therapies or treatment of nonhepatic sites were excluded. Included publications were critically appraised on quality and their results reported accordingly. Results Seven publications were included in this review, including a total of 114 patients treated IA with different types of radiopeptides. Objective response was seen in 13 to 69% of the patients and disease stabilization in 18 to 52%. Disease progression occurred in 0 to 29% of the patients. IA administration resulted in a 1.06 to 9.2-fold increase in tumor-to-nontumor dose ratios in liver tumors, while normal liver and kidney doses remained within expected ranges. The incidence of adverse events was comparable to IV administration. Conclusion There is limited evidence that IA application of PRRT results in higher tumor-to-non-tumor dose ratios compared with IV infusion. IA administration of 177Lu-DOTATATE seems to be a promising new improvement in current clinical practice, achieving a higher absorbed tumor dose in patients with hepatic metastases of NEN.

426 MK-3475-U02: Phase 1/2 study of investigational agents with or without pembrolizumab versus pembrolizumab monotherapy in melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A451-A451
Author(s):  
Reinhard Dummer ◽  
Georgina V Long ◽  
Anna Pavlick ◽  
Michael Postow ◽  
Antoni Ribas ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Adaptive Design ◽  
Phase 1 ◽  
Objective Response ◽  
End Points ◽  
Investigational Agent ◽  
Link Type ◽  
Programmed Death ◽  
Investigational Agents ◽  
Study Intervention

BackgroundPembrolizumab is a standard of care for the treatment of unresectable or metastatic melanoma and an adjuvant treatment of melanoma with involvement of lymph node(s) following complete resection. However, new treatment options are needed to reduce the tumor burden before surgery and improve overall outcomes in patients with advanced melanoma.MethodsMK-3475-U02 is a phase 1/2, rolling arm, multicenter, open-label, adaptive design study to evaluate the safety and efficacy of investigational agents with or without pembrolizumab or pembrolizumab alone for the treatment of melanoma. Patients will be enrolled in 1 of the 3 substudies. Substudy 02A will include patients with programmed death-1 (PD-1)–refractory melanoma (progressed after ≥2 doses of anti-PD-1/programmed death ligand-1 [PD-L1] therapy) randomized equally to treatment arms evaluating ≥1 investigational agent(s) with or without pembrolizumab. Enrollment is planned for up to ~100 patients per arm.Substudy 02B will include patients with unresectable stage III or stage IV melanoma not amenable to local therapy. Patients will be randomized 2:1 to combination (≥1 investigational agent(s) with or without pembrolizumab) or monotherapy (pembrolizumab alone) stratified by baseline lactate dehydrogenase status (normal/elevated) and prior adjuvant therapy with a PD-1 inhibitor (yes/no). Enrollment is planned for ~90 patients in the combination arm and ~45 in the control arm.Substudy 02C will include patients with stage IIIB/IIIC/IIID melanoma who are candidates for neoadjuvant therapy. Patients will be randomly assigned to combination (≥1 investigational agent(s) with or without pembrolizumab) or monotherapy (pembrolizumab alone). Surgical resection will be performed 6 weeks after the first dose of neoadjuvant study intervention. Enrollment is planned for ~25 patients in combination and ~15 in the pembrolizumab monotherapy arms.Treatment will continue for up to 2 years (up to 1 year neoadjuvant/adjuvant therapy for substudy 02C), until disease progression, unacceptable toxicity, or study discontinuation. The primary end points include safety (adverse events and study intervention discontinuations) for all 3 substudies; objective response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumors 1.1 for substudies 02A and 02B, and pathological complete response (pCR) as assessed by central review of the pathology results for substudy 02C. Secondary end points include duration of response for substudies 02A and 02B, and recurrence-free survival, near pCR, and pathological partial response rates for substudy 02C.ResultsN/AConclusionsN/AAcknowledgementsThe authors thank the patients and their families for participating in these trials and all investigators and site personnel. Medical writing and/or editorial assistance was provided by Neha Tuli-Wildemore, MBBS, PhD, and Doyel Mitra, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT04305041, NCT04305054, NCT04303169Ethics ApprovalThe study protocol and all amendments were approved by the relevant Institutional Review Board or ethics committee at each study site. All patients provided written informed consent to participate in the clinical trial.ConsentN/AReferencesN/A

403 Early results from a phase 1 study to evaluate safety, pharmacokinetics, and efficacy of AMG 404, a programmed death-1 (PD-1) antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A428-A428
Author(s):  
Timothy Price ◽  
Sant Chawla ◽  
Gerald Falchook ◽  
Hans Prenen ◽  
Iwona Lugowska ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
Clear Cell ◽  
Phase 1 ◽  
Cell Cancer ◽  
Objective Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Advanced Solid Tumors

BackgroundEnhancement of antitumor immunity through inhibition of the checkpoint PD-1 receptor has been effective in the treatment of many malignancies. AMG 404 is a monoclonal antibody (mAb) targeting PD-1. This phase 1, open-label, multicenter first-in-human study (NCT03853109) will evaluate the safety, tolerability, pharmacokinetics, and efficacy of AMG 404 monotherapy in adult patients with advanced solid tumors.MethodsThe primary study endpoint is dose-limiting toxicity (DLT) and safety; key secondary endpoints include pharmacokinetic parameters, objective response rate (assessed Q8W), duration of response, and progression-free survival. Key inclusion criteria include histologically or cytologically proven metastatic or locally advanced solid tumors not amenable to curative treatment with surgery or radiation for which standard therapies have been exhausted or not available. Prior anti-PD-(L)1 or other checkpoint inhibitors were not allowed. Five dose-finding cohorts, including 2 expansion cohorts, ranged from 3–20 patients each. AMG 404 was given until disease progression, intolerance, or consent withdrawal.ResultsAs of the data cutoff date of May 4, 2020, 62 patients received at least 1 dose of AMG 404 and were included in the safety and efficacy analysis sets. Fifty percent were men, 72% had ECOG 1 performance status, median age was 62 years (range: 28–83), and 42% had ≥3 lines of prior anticancer therapy. Median AMG 404 exposure was ~3 months (maximum: ~12 months). No DLTs were observed. Treatment-related adverse events (TRAEs) were reported for 29 patients (47%): those reported for ≥2 patients were fatigue (n=7); hypothyroidism (n=6); increased blood thyroid stimulating hormone and nausea (n=4 each); increased aspartate aminotransferase, decreased appetite, and pyrexia (n=3 each); and increased alanine aminotransferase, arthralgia, diarrhea, and increased weight (n=2 each). AEs leading to withdrawal of AMG 404 were reported for 3 patients (5%); all were serious and considered to be not related to AMG 404. Sixteen (26%) patients died on study; no deaths were considered related to AMG 404. Preliminary pharmacokinetic results were consistent with those of other therapeutic anti-PD-1 mAbs. Three patients had a confirmed partial response (pancreatic cancer, clear cell cancer, and pleomorphic sarcoma); an additional 4 patients had one scan with a partial response and are pending a confirmatory scan (clear cell renal carcinoma, undifferentiated nasopharyngeal carcinoma, sarcomatoid carcinoma of unknown primary, and colon cancer).ConclusionsAMG 404 is tolerable at the tested doses with no DLTs reported. All observed TRAEs are consistent with other anti-PD-1 therapies. Encouraging anti-tumor activity has been observed in heavily pretreated patients. The study is continuing enrollment into additional cohorts.Trial RegistrationNCT03853109Ethics ApprovalThe study was approved by the Ethics Board of each institution involved in this study and can be produced upon request.

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