A phase III randomized study comparing perioperative nivolumab vs. observation in patients with localized renal cell carcinoma undergoing nephrectomy (PROSPER RCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS710-TPS710
Author(s):  
Lauren Christine Harshman ◽  
Maneka Puligandla ◽  
Naomi B. Haas ◽  
Mohamad Allaf ◽  
Charles G. Drake ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Clinical Stage ◽  
Expression Patterns ◽  
Randomized Study ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Phase Iii ◽  
Current Standard ◽  
Tumor Biopsy ◽  
Absolute Increase

TPS710 Background: The anti-PD-1 antibody nivolumab (nivo) improves overall survival (OS) in metastatic treatment refractory RCC and is generally tolerable. In 2017, there is no standard adjuvant therapy proven to increase OS over surgery alone in non-metastatic (M0) disease. Mouse solid tumor models have revealed an OS benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivo in RCC patients (pts) are showing preliminary feasibility and safety with no surgical delays/complications. PROSPER RCC will examine if the addition of perioperative nivo to radical or partial nephrectomy can improve clinical outcomes in pts with locally advanced RCC. We are implementing a three-pronged, multidisciplinary approach of presurgical priming with nivo followed by resection and adjuvant PD-1 blockade with the goal of increasing cure and recurrence-free survival (RFS) rates in M0 RCC. Methods: Tumor biopsy prior to randomization is mandatory to ensure RCC diagnosis but will also permit unparalleled correlative science in this global, unblinded, phase 3 National Clinical Trials Network randomized study. 766 pts with clinical stage ≥T2 or any node positive M0 RCC of any histology will be enrolled. The study arm will receive nivo 240mg IV for 2 doses prior to surgery followed by adjuvant dosing for 9 mo (q2 wks x 3 mo followed by q4 wks x 6 mo). The control arm will undergo the current standard of care: surgical resection followed by observation. Pts are stratified by clinical T stage, node positivity, and histology. There is 84.2% power to detect a 14.4% absolute increase in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 yrs (HR 0.70). The study is also powered to detect a significant OS benefit (HR 0.67). Safety, feasibility, and quality of life are key secondary endpoints. PROSPER RCC exemplifies team science and incorporates a host of correlative work to examine the significance of the baseline immune milieu and changes induced by neoadjuvant priming and to identify predictive gene expression patterns. New collaborations welcomed. Clinical trial information: NCT03055013.

A phase III randomized study comparing perioperative nivolumab vs. observation in patients with localized renal cell carcinoma undergoing nephrectomy (PROSPER RCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4596-TPS4596 ◽  
Author(s):  
Lauren Christine Harshman ◽  
Maneka Puligandla ◽  
Naomi B. Haas ◽  
Mohamad Allaf ◽  
Charles G. Drake ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Clinical Stage ◽  
Expression Patterns ◽  
Correct Diagnosis ◽  
Randomized Study ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Phase Iii ◽  
Current Standard ◽  
Absolute Increase

TPS4596 Background: The anti-PD-1 antibody nivolumab (nivo) improves overall survival (OS) in metastatic treatment refractory RCC and is generally tolerable. In 2017, there is no standard adjuvant therapy proven to increase OS over surgery alone in non-metastatic (M0) disease. Mouse solid tumor models have revealed an OS benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivo in RCC patients (pts) have shown preliminary feasibility and safety with no surgical delays or complications. The PROSPER RCC trial will examine if the addition of perioperative nivo to radical or partial nephrectomy can improve clinical outcomes in pts with locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in M0 RCC, we propose a three-pronged, multidisciplinary approach of presurgical priming with nivo followed by resection and adjuvant PD-1 blockade. Methods: Tumorbiopsy prior to randomization is mandatory to ensure the correct diagnosis and will permit unparalleled correlative science in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. 766 pts with clinical stage ≥T2 or any node positive M0 RCC of any histology will be enrolled. The study arm will receive nivo 240mg IV for 2 doses prior to surgery followed by nivo adjuvantly for 9 months (q2 wks x 3 mo followed by q4 wks x 6 mo). The control arm will undergo the current standard of care: surgical resection followed by observation. Pts are stratified by clinical T stage, node positivity, and histology. There is 84.2% power to detect a 14.4% absolute increase in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 yrs (HR 0.70). The study is also powered to detect a significant OS benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the significance of the baseline immune milieu and changes after neoadjuvant priming and to identify predictive gene expression patterns. Additional collaborations are welcomed.

PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4596-TPS4596
Author(s):  
Mohamad E. Allaf ◽  
Se Eun Kim ◽  
Viraj A. Master ◽  
David F. McDermott ◽  
Sabina Signoretti ◽  
...  
Keyword(s):  
Immune System ◽  
Clinical Outcomes ◽  
Clinical Stage ◽  
Randomized Study ◽  
Standard Of Care ◽  
Phase Iii ◽  
Perioperative Therapy ◽  
Tumor Biopsy ◽  
Care Surgery ◽  
Metastatic Rcc

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5101-TPS5101
Author(s):  
Naomi B. Haas ◽  
Maneka Puligandla ◽  
Mohamad E. Allaf ◽  
David F. McDermott ◽  
Charles G. Drake ◽  
...  
Keyword(s):  
Immune System ◽  
Clinical Outcomes ◽  
Clinical Stage ◽  
Randomized Study ◽  
Standard Of Care ◽  
Phase Iii ◽  
Perioperative Therapy ◽  
Tumor Biopsy ◽  
Care Surgery ◽  
Metastatic Rcc

TPS5101 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 2020, 396 patients have been enrolled. Clinical trial information: NCT03055013 .

Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix

2011 ◽  
Vol 29 (13) ◽  
pp. 1678-1685 ◽  
Author(s):  
Alfonso Dueñas-González ◽  
Juan J. Zarbá ◽  
Firuza Patel ◽  
Juan C. Alcedo ◽  
Semir Beslija ◽  
...  
Keyword(s):  
External Beam Radiotherapy ◽  
Randomized Study ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Karnofsky Performance Score ◽  
Current Standard ◽  
Open Label ◽  
Grade 3

Purpose To determine whether addition of gemcitabine to concurrent cisplatin chemoradiotherapy and as adjuvant chemotherapy with cisplatin improves progression-free survival (PFS) at 3 years compared with current standard of care in locally advanced cervical cancer. Patients and Methods Eligible chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease and Karnofsky performance score ≥ 70 were randomly assigned to arm A (cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 weekly for 6 weeks with concurrent external-beam radiotherapy [XRT] 50.4 Gy in 28 fractions, followed by brachytherapy [BCT] 30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m2 on day 1, plus gemcitabine, 1,000 mg/m2 on days 1 and 8) or to arm B (cisplatin and concurrent XRT followed by BCT only; dosing same as for arm A). Results Between May 2002 and March 2004, 515 patients were enrolled (arm A, n = 259; arm B, n = 256). PFS at 3 years was significantly improved in arm A versus arm B (74.4% v 65.0%, respectively; P = .029), as were overall PFS (log-rank P = .0227; hazard ratio [HR], 0.68; 95% CI, 0.49 to 0.95), overall survival (log-rank P = .0224; HR, 0.68; 95% CI, 0.49 to 0.95), and time to progressive disease (log-rank P = .0012; HR, 0.54; 95% CI, 0.37 to 0.79). Grade 3 and 4 toxicities were more frequent in arm A than in arm B (86.5% v 46.3%, respectively; P < .001), including two deaths possibly related to treatment toxicity in arm A. Conclusion Gemcitabine plus cisplatin chemoradiotherapy followed by BCT and adjuvant gemcitabine/cisplatin chemotherapy improved survival outcomes with increased but clinically manageable toxicity when compared with standard treatment.

PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS765-TPS765 ◽  
Author(s):  
Lauren Christine Harshman ◽  
Maneka Puligandla ◽  
Mohamad E. Allaf ◽  
David F. McDermott ◽  
Charles G. Drake ◽  
...  
Keyword(s):  
Immune System ◽  
Clinical Outcomes ◽  
Clinical Stage ◽  
Randomized Study ◽  
Standard Of Care ◽  
Phase Iii ◽  
Perioperative Therapy ◽  
Tumor Biopsy ◽  
Care Surgery ◽  
Metastatic Rcc

TPS765 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of October 18, 2019, 317 patients have been enrolled. Clinical trial information: NCT03055013.

Multicenter randomized controlled phase III study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS6095-TPS6095
Author(s):  
Chia-Jung Busch ◽  
Adrian Muenscher ◽  
Christian Stephan Betz ◽  
Volkan Dogan ◽  
Philippe Schafhausen ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Distant Metastasis ◽  
Tumor Antigens ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Late Toxicity ◽  
Standard Of Care ◽  
Phase Iii ◽  
Free Survival ◽  
Treatment Naïve

TPS6095 Background: Surgically treated locally advanced head and neck squamous cell carcinoma (LA HNSCC) often requires postoperative chemoradiation with high risk of acute and late toxicity. Disease-free survival (DFS) after 2 years is approximately 70%. Combining Nivolumab (N), a PD-1inhibitor, and Ipilimumab, a CTLA4 inhibitor, as maintenance therapy may improve DFS due to anti-tumor effects of immunotherapy by enhancing cross-presentation of tumor antigens. The IMSTAR HN study compares neoadjuvant N and N±I 6 months after adjuvant therapy vs the standard therapy as first-line treatment for LA HNSCC. Methods: Eligible pts are ≥18 years old with treatment-naive LA HNSCC (oral cavity, oropharynx p16-, hypopharynx, and larynx), ECOG PS ≤1, and no distant metastasis. 276 pts will be randomized (2:1) into 2 arms and approximately 10 centers in Germany will be involved. Standard of care (arm II) consists of surgical resection followed by risk-adapted adjuvant (chemo)radiation. The experimental arm I receives neoadjuvant N 3mg/kg. After treatment according to standard arm a second randomization will be performed: In arm Ia N 3mg/kg will be given every 2 weeks until progression or up to 6 months. In arm Ib I 1mg/kg will be applied additionally every 6 weeks also until progression or up to 6 months. Primary endpoints is DFS in arms I and II. Secondary endpoints: Local regional control (LRC), distant metastasis free survival (DMFS), overall survival (OS), quality of life (QoL), survival depending on PD-L1 status, comparison of arm Ia vs arm II and Ib vs. II. AEs, graded per CTCAE v4.03, are evaluated for at least 12 months after randomization. The translational program includes investigations concerning immunmodulation, mutational load in general, but also specific mutations in targets involved in immune function and antigen presentation. Recruitment started in August 2018. Clinical trial information: NCT03700905.

scholarly journals A Primer on the Current State-of-the-Science Neoadjuvant and Adjuvant Therapy for Patients with Locally Advanced Rectal Adenocarcinomas

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jeffrey T. Yorio ◽  
Nishin A. Bhadkamkar ◽  
Bryan K. Kee ◽  
Christopher R. Garrett
Keyword(s):  
Adjuvant Therapy ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Current Standard ◽  
Colon Cancers ◽  
Standard Of Care Treatment ◽  
Rectal Cancers ◽  
State Of The Science

Patients with rectal cancers, due to the unique location of the tumor, have a recurrence pattern distinct from colon cancers. Advances in adjuvant therapy over the last three decades have played an important role in improving patient outcomes. This article serves to review the clinical studies that lay the basis for our current standard-of-care treatment of patients with locally advanced rectal cancer, as well as touch upon future ongoing experimental clinical trials of adjuvant chemoradiation therapy.

Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)- eligible cohort of HCRN GU14-188.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5047-5047
Author(s):  
Christopher J. Hoimes ◽  
Nabil Adra ◽  
Mark T. Fleming ◽  
Hristos Z. Kaimakliotis ◽  
Joel Picus ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Standard Of Care ◽  
Phase Iii ◽  
Current Standard ◽  
Primary Analysis ◽  
Term Survival ◽  
Phase 1B ◽  
Elevated Creatinine ◽  
Muscle Invasive ◽  
Minimum Criteria

5047 Background: Patients (pts) with laUC who are C-eligible for N- therapy may benefit from combination chemo-immunotherapy. Cohort 1 (C1) of the GU14-188 trial is a phase 1b/2 trial designed to assess the tolerability and efficacy of N- gemcitabine (G), C, and P in pts with laUC. The current standard of care is ddMVAC with a pathologic non-muscle invasive rate (PaIR, ≤pT1N0) of ~44%. Methods: Eligible pts for C1 were surgical candidates and C-eligible with cT2-4aN0M0 bladder UC. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Phase 1b (no DLT) /2 treatments were the same: P 200mg q3wks on day 8 x5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21 day cycle (cy), for 4 cy; followed by radical cystectomy (RC). Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of PaIR was assessed at RC and designed for 86% power with 4% significance to detect a difference from 23 to 48%. Secondary endpoints include relapse free survival and overall survival. Results: 43 pts were enrolled to C1 with a median (mdn) age 64, 63% male, 51% > cT2. Mdn per-pt doses given (attempted) for: P:5(5), C:4(4), G:8(8). The PaIR was 61.1% (95%CI 0.45, 0.75), P0 (ypT0N0) rate of 44.4%, and did not correlate with baseline PD-L1 score. Downstage to PaIR occurred in 53% of cT2, and 74% of cT3/4. Mdn time to RC from last dose was 5.3wks. Seven were not included in the primary analysis: 4 (9.3%) without RC, 1 progressed, 1 lost to f/u during C1, 1 did not receive required protocol therapy. There was 1 death on post-RC day 9 due to mesenteric ischemia. Of 4 pts who did not have RC, 3 refused and 1 due to gr4 thrombocytopenic purpura; 4pts are alive and without recurrence at mdn f/u of 32mo. One pt with presumed gr3 MI during cy 4 had a negative inpt cardiac workup and completed therapy and RC without further AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. At mdn f/u of 34.2mo (3.9-47.4), the estimated 36mo RFS, OS, and DSS is 63%, 82%, and 87%, respectively. Conclusion: Neoadjuvant GC with P in laUC has manageable toxicity and has improved pathologic outcomes compared to historic controls. Durable long-term survival in those with- and without -RC is noteworthy in this advanced cohort. KEYNOTE 866, NCT03924856, is a Phase III study of GC with perioperative P. Clinical trial information: NCT02365766 .

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