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.

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 .

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.

ZUMA-8: A phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7566-TPS7566 ◽  
Author(s):  
Ian Flinn ◽  
Michael Marris ◽  
William G. Wierda ◽  
Steven Coutre ◽  
John M. Pagel ◽  
...  
Keyword(s):  
High Risk ◽  
Multicenter Study ◽  
Residual Disease ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
T Cell Therapy ◽  
Patient Reported

TPS7566 Background: Despite treatment advances, CLL is largely incurable. First-line targeted therapy with ibrutinib mostly produces durable remissions, but high-risk disease or many prior therapies increases relapse risk (Ghia P, et al. Haematologica. 2014). Relapse after ibrutinib is associated with a poor outcome (Maddocks KJ, et al. JAMA Oncol. 2015). Allogeneic stem cell transplantation potentially offers long-term remissions but has a high risk of morbidity/mortality (Shustik C, et al. Ann Hematol. 2017). Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) with a CD28 costimulatory domain may be efficacious against CLL (Kochenderfer JN, et al. Blood. 2012). KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for R/R hematologic malignancies and may offer longer durable remissions with manageable safety in pts with R/R CLL. ZUMA-8 is a Phase 1/2 multicenter study for pts with R/R CLL. Methods: Adult pts must have R/R CLL with ≥ 2 prior treatment regimens, disease progression on ibrutinib, ECOG 0-1, and adequate organ function. Phase 1 will enroll 12-18 pts to assess dose-limiting toxicities (DLTs) with a 6 + 3 dose escalation/de-escalation design; 30 more pts may be enrolled to further assess safety. Phase 2 will enroll ≈60 pts to evaluate efficacy and safety. Pts will undergo leukapheresis followed by optional bridging therapy. Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) conditioning chemotherapy will be given on Days -5, -4 and -3. KTE-X19 will be given on Day 0 at 0.5, 1 or 2 × 106 KTE-X19 cells/kg. The primary endpoint is incidence of DLTs for Phase 1 and independent review committee-assessed objective response rate (ORR) per iwCLL 2018 criteria for Phase 2. Secondary endpoints include complete remission (CR) rate, investigator-assessed ORR, minimal residual disease (MRD) negativity rate, MRD-negative CR rate, duration of response, progression-free survival, overall survival, safety, and patient-reported outcomes (Phase 2). Serum cytokine and blood KTE-X19 cell levels over time and level of anti-KTE-X19 antibodies are exploratory endpoints. Accrual is ongoing. Clinical trial information: NCT03624036.

A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4693-TPS4693 ◽  
Author(s):  
Robert Dreicer ◽  
David B. Agus ◽  
Joaquim Bellmunt ◽  
Johann Sebastian De Bono ◽  
Daniel Peter Petrylak ◽  
...  
Keyword(s):  
Disease Progression ◽  
Fusion Gene ◽  
Phase 1 ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase Iii ◽  
Double Blind ◽  
Investigational Agent ◽  
Patient Reported ◽  
To Receive

TPS4693 Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after receiving a total of ≥360 mg/m2 docetaxel within a 6-mo period. Patients who are clearly intolerant to docetaxel or have progressive disease before receiving ≥360 mg/m2 are also eligible if they have received at least 225 mg/m2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility criteria include radiographically documented metastatic disease and baseline testosterone <50 ng/dL following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell and endocrine marker changes, and patient-reported outcomes. After disease progression, men may continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).

Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5094-TPS5094 ◽  
Author(s):  
Toni K. Choueiri ◽  
Laurence Albiges ◽  
Li Fan ◽  
Rodolfo F. Perini ◽  
Naseem J. Zojwalla ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Prognostic Scores ◽  
Phase Iii ◽  
Once Daily ◽  
Patient Reported ◽  
Previously Treated ◽  
Metastatic Rcc

TPS5094 Background: In RCC, the Von Hippel-Lindau ( VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2α. HIF-2α is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A ( VEGFA), cyclin D1, and CXCR4. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged ≥18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received ≤3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor (≥2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750 .

scholarly journals Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial

2016 ◽  
Vol 34 (8) ◽  
pp. 786-793 ◽  
Author(s):  
George D. Demetri ◽  
Margaret von Mehren ◽  
Robin L. Jones ◽  
Martee L. Hensley ◽  
Scott M. Schuetze ◽  
...  
Keyword(s):  
Disease Control ◽  
Objective Response ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Prior Therapy ◽  
Risk Of Death ◽  
End Point ◽  
Patient Reported

Purpose This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. Patients and Methods Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control—progression-free survival (PFS), time to progression, objective response rate, and duration of response—as well as safety and patient-reported symptom scoring. Results A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. Conclusion Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.

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 .

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