A phase Ib clinical trial of neoadjuvant OrienX010, an oncolytic virus, in combination with toripalimab in patients with resectable stage IIIb to stage IVM1a acral melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9570-9570
Author(s):  
Xuan Wang ◽  
Chuanliang Cui ◽  
Lu Si ◽  
Caili Li ◽  
Jie Dai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Oncolytic Virus ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Neoadjuvant Treatment ◽  
Stage Iiib ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Phase Ib ◽  
Acral Melanoma

9570 Background: Metastatic acral melanoma is very difficult to treat. Unlike cutaneous melanoma, acral melanoma responds poorly to checkpoint inhibitors in monotherapy. OrienX010 is a granulocyte-macrophage colony-stimulating factor expressing herpes simplex type-1 derived oncolytic virus. It has shown robust efficacy in metastatic acral melanoma, and may improve the response to checkpoint inhibitors. To evaluate the role of OrienX010 in combination with checkpoint inhibitors in acral melanoma, we conducted a Phase Ib neoadjuvant trial of OrienX010 in combination with the anti-PD-1 monoclonal antibody toripalimab in resectable stage IIIB-IVM1a acral melanoma (NCT04197882). Methods: Patients with resectable stage IIIB-IV M1a acral melanoma received neoadjuvant intratumoral OrienX010 up to 10 mL of 8 x 107 pfu/mL and intravenous toripalimab 3 mg/kg every 2 weeks for 4 – 6 doses prior to surgical resection. After resection, adjuvant toripalimab 3 mg/kg was administered every 3 weeks for up to 1 year. The primary endpoints were radiographic response rate per RECIST 1.1 and pathological response rate (pCR and pPR). The secondary endpoints were 1- and 2-year recurrence-free survival, and safety. Results: Between July 2019 and Jan 2021, 30 patients with regional metastatic acral melanoma were enrolled. Median age was 56.5 years, 14 (47%) were male, 19 (63%) had recurrent disease, and stage IIIB 12 (40%), IIIC 14 (47%), and IVM1a 4 (13%). Median tumor burden was 28mm (range, 10-80mm), and only 5 (17%) patients had melanoma mutations (2 cKIT, 1 NRAS, 2 BRAF). To date, of 24 patients who completed neoadjuvant treatment, 21 (88%) underwent surgery. Three (12%) patients did not undergo surgery due to disease progression prior to surgery and 6 patients are still receiving neoadjuvant treatment. Radiographic responses were seen in 10 (33%) patients. However, 17 of 21 (81%) patients showed pathologic responses in resected metastases, with 3 (14%) showing a pCR and 14 (67%) a pPR. Pathologic responses were associated with greater lymphoid infiltrate, hyaline fibrosis, and decrease in Ki-67 expression in the metastasis. At a median follow-up of 8.9 months, none of the patients who underwent resection have recurred. The neoadjuvant treatment was well tolerated, with all patients experiencing at least 1 treatment related adverse event (TRAE) and Grade 1 fever was most common. Three (10%) patients had a grade 3-4 TRAE, including 1 alanine aminotransferase increase and 2 wound infections. Conclusions: Neoadjuvant treatment with OrienX010 and toripalimab in resectable stage IIIB-IVM1a acral melanoma was well tolerated and produced a high pathologic response rate. To date, no patients have recurred, and recurrence-free survival evaluation is ongoing. This combination therapy warrants further evaluation in acral melanoma. Clinical trial information: NCT04197882.

scholarly journals Current Melanoma Treatments: Where Do We Stand?

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 221
Author(s):  
Alvaro Moreira ◽  
Lucie Heinzerling ◽  
Nina Bhardwaj ◽  
Philip Friedlander
Keyword(s):  
Clinical Trials ◽  
Cancer Biology ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Care ◽  
Neoadjuvant Treatment ◽  
Treatment Modalities ◽  
Recurrence Free Survival ◽  
Survival Curves ◽  
Free Survival

Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma.

Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer.

1995 ◽  
Vol 13 (3) ◽  
pp. 547-552 ◽  
Author(s):  
T J Powles ◽  
T F Hickish ◽  
A Makris ◽  
S E Ashley ◽  
M E O'Brien ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Adjuvant Therapy ◽  
Randomized Trial ◽  
Response Rate ◽  
Neoadjuvant Treatment ◽  
Operable Breast Cancer ◽  
Chemoendocrine Therapy ◽  
Primary Operable Breast Cancer

PURPOSE To evaluate in a randomized clinical trial systemic chemoendocrine therapy used as primary (neo-adjuvant) treatment before surgery in women with primary operable breast cancer. PATIENTS AND METHODS Patients aged less than 70 years with clinically palpable, primary operable breast cancer diagnostically confirmed by fine-needle aspiration cytology (FNAC) and suitable for treatment with surgery, radiotherapy, cytotoxic chemotherapy, and tamoxifen were considered eligible. Patients randomized to neoadjuvant treatment received four cycles of chemo-therapy for 3 months before surgery followed by another four cycles after surgery, and were compared with patients randomized to adjuvant therapy who received eight cycles of chemotherapy over 6 months after surgery. RESULTS Of 212 patients who were randomized to receive either adjuvant (n = 107) or neoadjuvant (n = 105) chemoendocrine therapy, 200 are now assessable for response. The two groups are comparable for age, menopausal status, disease stage, and surgical requirements. The overall clinical response rate was 85%, with a complete histologic response rate of 10%. There was a significant reduction in the requirement for mastectomy in patients who received neoadjuvant treatment (13%) as compared with those who received adjuvant therapy (28%) (P < .005). Symptomatic and hematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. The median follow-up period for patients in this trial is 28 months, during which time four patients have relapsed locally and 20, including one of the local relapses, have developed metastatic disease, 19 of whom have died. The follow-up period is too brief to evaluate relapse rate or survival duration. CONCLUSION This trial confirms previous reports of a high rate of response to neoadjuvant therapy, but is the first to include small primary cancers and to show, in the context of a randomized trial, a reduction in the requirement for mastectomy. Until disease-free and overall survival data are available from the larger National Surgical Adjuvant Breast and Bowel Project (NSABP)-18 trial, such neoadjuvant treatment cannot be recommended outside of a clinical trial.

scholarly journals Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors

2020 ◽  
Vol 38 (27) ◽  
pp. 3088-3094 ◽  
Author(s):  
Anita Gul ◽  
Tyler F. Stewart ◽  
Charlene M. Mantia ◽  
Neil J. Shah ◽  
Emily Stern Gatof ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Free Survival ◽  
Metastatic Rcc

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

scholarly journals Most-enhancing tumor volume by MRI radiomics predicts recurrence-free survival “early on” in neoadjuvant treatment of breast cancer

2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Karen Drukker ◽  
Hui Li ◽  
Natalia Antropova ◽  
Alexandra Edwards ◽  
John Papaioannou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Volume ◽  
Neoadjuvant Treatment ◽  
Recurrence Free Survival ◽  
Free Survival

A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS394-TPS394 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Ralph de Vere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Androgen Synthesis ◽  
Psa Response

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.

Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 542-542 ◽  
Author(s):  
Juan Francisco Rodriguez-Moreno ◽  
Guillermo de Velasco ◽  
Inmaculada Bravo Fernandez ◽  
Carlos Alvarez-Fernandez ◽  
Ricardo Fernandez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Molecular Characterization ◽  
Biomarker Discovery ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Neoadjuvant Treatment ◽  
Molecular Profile ◽  
Efficacy And Safety ◽  
The Impact

542 Background: Cisplatin-based chemotherapy remains the perioperative treatment in muscle-invasive bladder carcinoma (MIBC). Recent evidence suggests that immune checkpoint inhibitors could be incorporated in this setting. Olaparib is a PARP inhibitor with well-established activity in HRD tumor. Results from trials assessing the combination of durvalumab and olaparib suggest a synergistic effect. However, a molecular characterization is crucial to warrant a rational development. Methods: A phase II clinical trial was designed to assess the impact of neoadjuvant treatment with the combination of durvalumab plus olaparib in the molecular profile of MIBC (NCT03534492; SOGUG-2017-A-IEC(VEJ)-2). Efficacy and safety were secondary objectives. Subjects with cT2-T4a MIBC aimed for cystectomy were treated during 6 to 8 weeks pre-cystectomy. Diagnostic and surgical samples, pre and postreatment blood samples have been collected for the molecular analysis. We present results regarding efficacy and safety. Results: From November 2018 to October 2019 28 patients have been enrolled. 52%/48% of patients had PS 0/1. Median age was 70. TNM stage was: pT2 in 73,6% patients, pT3 in 10.6%, pT4 in 15.8% and 10.6% presented nodal spread. 13 patients have completed neoadjuvant treatment so far and 12 have undergone cystectomy. A wound dehiscence and one death related to surgical procedures were postoperative complications. Pathological complete response rate is 44,5%. Radiological evaluation is ongoing. 10 serious adverse events non-treatment related have been communicated. Any grade of toxicity has been reported in 91% of patients but adverse events grade 3-4 was detected in only 8.3% of cases. Grade 1 pruritus was the unique IR adverse event described in one patient. PARP inhibitors-related adverse events were grade 1 nausea and vomiting (25%), and grade 1 anemia (25%). Conclusions: Preliminary clinical data suggest that Durvalumab in combination with Olaparib could be active and well-tolerated neoadjuvant treatment of MIBC. Molecular characterization and biomarker discovery will be presented separately. Clinical trial information: NCT03534492.

Relapse-free survial and target identification to enhance response with neoadjuvant and adjuvant dabrafenib + trametinib (D+T) treatment compared to standard-of-care (SOC) surgery in patients (pts) with high-risk resectable BRAF-mutant metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9587-9587 ◽  
Author(s):  
Jennifer Ann Wargo ◽  
Rodabe Navroze Amaria ◽  
Peter A. Prieto ◽  
Miles Cameron Andrews ◽  
Michael T. Tetzlaff ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Metastatic Melanoma ◽  
Response Rate ◽  
Mapk Pathway ◽  
Pathologic Complete Response ◽  
Stage Iv ◽  
Complete Response ◽  
Stage Iiib ◽  
Braf Mutant

9587 Background: Targeted and immune therapies have dramatically improved outcomes in stage IV metastatic melanoma pts. These agents are now being tested in earlier-stage disease. SOC surgery for high-risk resectable melanoma (AJCC stage IIIB/IIIC), with or without adjuvant therapy, is associated with a high risk of relapse (~70%). We hypothesized that neoadjuvant (neo) + adjuvant treatment with D+T improves RFS in these pts. Longitudinally collected biospecimens from pts receiving this treatment were analyzed to identify candidate strategies to further improve outcomes. Methods: A prospective single-institution randomized clinical trial (NCT02231775) was conducted in BRAF-mutant pts with resectable Stage IIIB/C or oligometastatic stage IV melanoma. Pts were randomized 1:2 to SOC (Arm A) versus neo + adjuvant D+T (Arm B; 8 wks neo + 44 wks adjuvant). The primary endpoint was RFS. Tumor biopsies were collected at baseline, week 3, and at surgery for molecular and immune profiling (whole exome sequencing, gene expression profiling, IHC, flow cytometry). Results: 21 of a planned 84 patients were enrolled (Arm A = 7, Arm B = 14). Arms were well balanced for standard prognostic factors, and toxicity was manageable. RECIST response rate with neo D+T was 77%, and the pathologic complete response rate (pCR) was 58%. First interim analysis revealed significantly improved RFS in the D+T arm over SOC (HR 62.5, p < 0.0001), leading to early closure to enrollment. Pts with a pCR at surgery had significantly improved RFS versus pts without pCR (p = 0.04) on neo D+T. Tumor profiling revealed incomplete MAPK pathway blockade and higher levels of CD8+ T cells expressing immunomodulators Tim-3 and Lag-3 in pts who did not achieve a pCR. Conclusions: Neo + adjuvant D+T is associated with a high pCR rate and markedly improved RFS over SOC in pts with high-risk resectable BRAF-mutant metastatic melanoma. pCR at surgery is associated with improved RFS. Tumor analyses reveal candidate targets for testing in future trials to enhance responses to neo D+T. Clinical trial information: NCT02231775.

A sequential dual cohort phase II clinical trial on adjuvant low-dose nivolumab with or without low-dose ipilimumab as adjuvant therapy following the resection of melanoma macrometastases (MM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9585-9585 ◽  
Author(s):  
Julia Katharina Schwarze ◽  
Valerie Vandersleyen ◽  
Gil Awada ◽  
Yanina Jansen ◽  
Teofila Seremet ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adjuvant Therapy ◽  
Low Dose ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Stage Iv ◽  
Complete Resection ◽  
Stage Iii ◽  
Fixed Dose ◽  
Free Survival

9585 Background: Optimal dosing and duration of adjuvant treatment with anti-PD-1 checkpoint inhibitors, e.g. nivolumab (NIVO), following complete resection of melanoma (MEL) lymph node metastases has not been established. We investigated a regimen of low-dose NIVO with/without low-dose ipilimumab (IPI) as adjuvant therapy in MEL pts. Methods: After complete resection of MM, pts were treated with IPI 50mg (fixed dose, 1x) plus NIVO 10mg (fixed dose, Q2w x4) (Cohort-A), or NIVO 10mg (Q2w x9, Q8w x4) (Cohort-B). One-year relapse-free survival (RFS) rate served as primary endpoint. Sample size (34 pts) was calculated according to a Fleming one-stage clinical trial design. Recruitment to Cohort-B was closed prematurely following registration of NIVO in the adjuvant setting by EMA. Secondary endpoints were safety, distant metastasis-free survival (DMFS) and overall survival (OS). Quantitative measurement of BRAF/ NRAS mutant circulating tumor DNA (ctDNA), as well as tumor gene expression profiling were performed. Results: 34 pts (15M/19F, 31 stage III/3 stage IV) and 22 pts (12M/10F, 21 stage III/1 stage IV) were enrolled in Cohort-A/-B, respectively. After a median follow-up of 86w for Cohort-A and 36w for Cohort-B, estimated 12 months (m) RFS-rate was respectively 55% (95% CI, 39–72) and 78% (95% CI, 73-82), 12m OS-rate was 97% (95% CI, 94-100) and 100%, and 12m DMFS-rate was 79% (95% CI, 92-65), no distant metastases occurred in Cohort-B. Median RFS for Cohort-A was 84w (95%, CI 28-139), not-reached in -B. Median DMFS and OS had not been reached at time of analysis in either cohort. All grade treatment-related adverse events were observed in 21 (61%)/17 (77%) with 3 (8%)/1 (4%) grade 3 irAE in Cohort-A/-B, respectively. One patient in Cohort-A had a detectable level of ctDNA at baseline and relapsed 33w after initiating treatment. Tumor profiling is ongoing at time of submission. Conclusions: The investigated adjuvant low-dose regimens have an acceptable safety profile. Survival rates resemble those of standard regimens. These regimens could be economically advantageous alternatives for pts without access to standard regimens. Clinical trial information: NCT02941744.

scholarly journals Immune Checkpoint Inhibitors in Advanced Acral Melanoma: A Systematic Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Qingyue Zheng ◽  
Jiarui Li ◽  
Hanlin Zhang ◽  
Yuanzhuo Wang ◽  
Shu Zhang
Keyword(s):  
Systematic Review ◽  
Combination Therapy ◽  
Objective Response Rate ◽  
Median Overall Survival ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Therapeutic Effects ◽  
Free Survival

IntroductionAcral melanoma (AM) has different biological characteristics from cutaneous melanoma. Although systemic therapeutic strategies for advanced AM resemble those for advanced cutaneous melanoma, the evidence of the clinical use of immune checkpoint inhibitors (ICIs) for AM is still inadequate. We aimed to systematically analyze the therapeutic effects and safety profile of ICI treatments in advanced AM.MethodsThis systematic review was conducted in line with a previously registered protocol. Three electronic databases, conference abstracts, clinical trial registers, and reference lists of included articles were searched for eligible studies. The primary outcomes were therapeutic effects, and the secondary outcomes were the safety profiles.ResultsThis systematic review included six studies investigating anti-CTLA-4 immunotherapy, 12 studies investigating anti-PD-1 immunotherapy, one study investigating the combination therapy of anti-CTLA-4 and anti-PD-1, and one study investigating anti-PD-1 immunotherapy in combination with radiotherapy. In most studies investigating ipilimumab, the anti-CTLA-4 antibody, the objective response rate ranged from 11.4 to 25%, the median progression-free survival ranged from 2.1 to 6.7 months, and the median overall survival was more than 7.16 months. For studies discussing anti-PD-1 immunotherapy with nivolumab, pembrolizumab, or JS001, the objective response rate ranged from 14 to 42.9%, the median progression-free survival ranged from 3.2 to 9.2 months, and the median overall survival was more than 14 months. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed better efficacy with an objective response rate of 42.9% than single-agent therapy. The retrospective study investigating the combination therapy of anti-PD-1 immunotherapy and radiation showed no overall response. Few outcomes regarding safety were reported in the included studies.ConclusionsICIs, especially anti-CTLA-4 monoclonal antibodies combined with anti-PD-1 antibodies, are effective systematic treatments in advanced AM. However, there remains a lack of high-level evidence to verify their efficacy and safety and support their clinical application.

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