Phase II study of sorafenib combined with gemcitabine and 5-fluorouracil in patients with metastatic renal cell carcinoma: Preliminary results

e16093 Background: The tyrosine kinase inhibitors sorafenib and sunitinib have been approved for use in patients with advanced RCC and have supplanted immunotherapy as first-line therapy. Nevertheless, complete responses have been observed only rarely with these agents and only 10% of patients experience PR. The vast majority of responding patients will ultimately progress despite continued therapy. In order to improve the objective response rate and the durability of those responses in patients, we conducted a single-institution, single-arm phase II trial of gemcitabine and 5-fluorouracil (5-FU) combined with sorafenib in patients with RCC. Methods: Eligibility criteria included advanced, histologically confirmed RCC; age >18 years; ECOG PS ≤ 2, adequate bone marrow, renal and hepatic function; measurable/evaluable lesions. Gemcitabine was administered at 1,000 mg/m2 over 30 min i.v. on days 1 and 8, followed by 5-FU 400 mg/m2 i.v. bolus on day 1 and 1,200 mg/m2/day × 2 days continuous infusion (28-day cycle). From day 1 of cycle 1, 400 mg sorafenib was continuously given twice daily. The sample size of 21 patients was sufficient to provide 80% power to detect an objective response rate that was greater than 10% with significance that 0.05 level. Results were expressed as mean±SD or median ± 95% CI. The primary study endpoint was objective response rate and the secondary were toxicity, progression-free survival and overall survival. Results: Patients (n = 21) were enrolled from May 2006 to Dec. 2007. The rate of objective response and disease control (including stable disease, complete responses and partial responses) were 38% (95% CI, 18–62%) and 86% (95% CI, 64–97%), respectively. Among them, there is 1 complete response and 2 pts occurred completely liquefaction deliquesce in metastatic lesions. The median PFS time is longer than 13 months, with 6/21 patients remaining progression free at 2008.12.26 the data were compiled for this report (three are longer than 26 months and there other three longer than 13 months ). The median OS time have not yet been reached, because of the amount of censoring data. Conclusions: The combination of sorafenib with gemcitabine and 5-FU shows promising activity for patients with metastatic RCC. No significant financial relationships to disclose.

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Phase II Results of Bendamustine in Combination with Rituximab in Relapsed Indolent and Mantle-Cell Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v108.11.2710.2710 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2710-2710 ◽

Cited By ~ 6

Author(s):

Richard H. Van der Jagt ◽

Philip Cohen ◽

Bruce D. Cheson ◽

Anil Tulpule ◽

Jordan A. Herst ◽

...

Keyword(s):

Phase Ii ◽

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

Prior Chemotherapy ◽

Non Hodgkin's Lymphoma ◽

Mantle Cell ◽

Grade 3

Abstract Objective: The objective of this study was to evaluate the efficacy and safety of bendamustine HCl (TREANDA®) in combination with rituximab in patients with relapsed non-Hodgkin’s lymphoma (NHL). Background: Bendamustine is a novel hybrid, alkylating agent with single-agent activity in multiple hematologic and solid tumors. It induces cell death via both apoptosis and the apoptosis-independent pathway of mitotic catastrophe. The combination of bendamustine and rituximab has been shown to exhibit a synergistic antitumor effect on NHL cells. Methods: This Phase II, multicenter study enrolled adult patients with relapsed, indolent B-cell or mantle-cell NHL who were not refractory to rituximab (defined as progression ≤6 months of last rituximab dose). Patients received rituximab 375 mg/m2 intravenously (IV) on day 1 and bendamustine 90 mg/m2 IV on days 2 and 3 of a 28-day cycle for 4 to 6 cycles. An additional dose of rituximab 375 mg/m2 IV was given 1 week before the first cycle of bendamustine and 4 weeks after the last cycle. Results: The intent-to-treat (ITT) population included 66 patients (59% men) with a median age of 60 years (range, 40–84). Indolent histologic phenotype was seen in 54 patients with the following histologic subtypes: follicular center cell (61%), small lymphocytic (15%), lymphoplasmacytic (3%), and marginal zone (3%); 18% had mantle-cell lymphoma (MCL). A total of 85% of patients had stage III/IV disease. These patients relapsed from a median of 1 prior chemotherapy (range: 0–5), with 56% having had prior treatment with rituximab. Patients with no prior chemotherapy relapsed following biologic therapy. In the ITT population, the overall objective response rate (ORR) was 94% (complete response [CR]/complete response unconfirmed [CRu], 41%; partial response [PR], 53%); 6% had stable disease. The ORR for the 12 MCL patients was 92% (CR/CRu, 42%; PR 50%). For all patients, the median duration of response and progression-free survival has not been reached after a median follow-up of 8.3 months (range, 0.14–31 months). Grade 3/4 neutropenia was seen in 41% of patients (7%, febrile neutropenia). Common nonhematologic toxicities (grade 1/2, grade 3, grade 4) were nausea (68%, 0%, 0%) and fatigue (53%, 5%, 0%); one patient had grade 3 sepsis. No alopecia was observed. Conclusions: Bendamustine administered in combination with rituximab produced a high objective response rate and was generally well tolerated in patients with relapsed indolent and mantle-cell NHL who were not refractory to rituximab. These results suggest that the combination of bendamustine and rituximab may be comparable in activity to R-CHOP, and further studies of this combination are warranted.

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Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.19.01389 ◽

2019 ◽

Vol 37 (34) ◽

pp. 3291-3299 ◽

Cited By ~ 35

Author(s):

Philippe Armand ◽

Scott Rodig ◽

Vladimir Melnichenko ◽

Catherine Thieblemont ◽

Kamal Bouabdallah ◽

...

Keyword(s):

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Complete Response ◽

End Points ◽

Free Survival ◽

Large B Cell Lymphoma ◽

Duration Of Response

PURPOSE Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

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Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy

Blood ◽

10.1182/blood.v98.13.3846 ◽

2001 ◽

Vol 98 (13) ◽

pp. 3846-3848 ◽

Cited By ~ 84

Author(s):

Thomas M. Moehler ◽

Kai Neben ◽

Axel Benner ◽

Gerlinde Egerer ◽

Fatime Krasniqi ◽

...

Keyword(s):

Multiple Myeloma ◽

Objective Response Rate ◽

Poor Prognosis ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

World Health ◽

Remission Induction

Abstract The feasibility and efficacy of a combination of thalidomide, cyclophosphamide, etoposide, and dexamethasone were studied in 56 patients with poor-prognosis multiple myeloma. Of 50 patients evaluable for response, 4% achieved complete response (CR), 64% partial response (PR), 18% minimal response (MR), 6% stable disease (SD), and 8% progressive disease (PD), resulting in an objective response rate (≥ MR) of 86.0% (76.7% overall objective response rate in intent-to-treat analysis; n = 56). Subsequent to successful remission induction, 18 patients received autologous or allogeneic stem cell transplantation. The median progression-free survival in all patients was 16 months. The median overall survival time could not be calculated, since the last observed death occurred after 16 months of follow-up (median follow-up of 14 months) with a corresponding estimated survival probability of 55%. Severe adverse effects (World Health Organization III/IV) included infectious complications (35.7%) and cardiovascular events (7.1%). The data suggest that Thal improves antitumor activity of salvage chemotherapy regimens in poor-prognosis multiple myeloma.

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Assessment of objective response rate (ORR) by investigator versus blinded independent central review in pivotal trials of drugs approved for solid tumor indications.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13570 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13570-e13570

Author(s):

Marjorie E. Zettler ◽

Choo H. Lee ◽

Ajeet Gajra ◽

Bruce A. Feinberg

Keyword(s):

Solid Tumors ◽

Solid Tumor ◽

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

Mean Difference ◽

Response To Treatment ◽

The Mean

e13570 Background: Objective response rate (ORR), defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST), is the most common endpoint used in pivotal trials supporting FDA approval of cancer drugs for solid tumor indications. Blinded independent central review (BICR) is frequently employed in clinical trials to minimize bias in evaluation of response rate, as historically, assessment of response by investigators (INV) has been shown to overestimate treatment effect. In this study, we analyzed the variability in assessment of ORR between INV and BICR in trials supporting recent Food and Drug Administration (FDA) approvals of drugs for solid tumor indications. Methods: The FDA’s novel drug approvals (2015-2019) were reviewed to identify drugs receiving primary approval for solid tumor indications. Drug approval packages accessed via the Drugs@FDA database and primary publications for the pivotal trials accessed via PubMed were reviewed for investigator-assessed and BICR-assessed ORR. For trials reporting both assessments, the difference between INV and BICR ORR was determined across all study arms. Data are presented using descriptive statistics. Results: A total of 36 drugs received primary approval for the treatment of solid tumors between 2015 and 2019. Of the 40 supporting trials, ORR was the primary endpoint for 21 (52.5%), progression-free survival for 13 (32.5%), and overall survival for 2 (5.0%). ORR was evaluated in 35 of the 40 trials (87.5%). Eight (22.9%) of the 35 trials evaluated INV ORR only, 5 (14.3%) evaluated BICR ORR only, and 22 (62.9%) evaluated both INV and BICR ORR. Among the 22 trials (29 arms in total), the mean difference between BICR- and INV-assessed ORR was -4.3% (95% CI: -6.4, -2.3); the range was -13.1 to 5. INV-assessed ORR was greater than BICR-assessed ORR in 22 of 29 arms (75.9%). The mean difference between BICR- and INV-assessed ORR among the 6 arms representing placebo or active control was -6.0 (95% CI: -11.0, -0.9), compared with -3.9 (95% CI: -6.3, -1.5) among the 23 experimental arms. Conclusions: Compared with BICR, INV overestimated ORR in three-quarters of the trial arms, including those representing control and experimental treatments. Despite this variability, for one fifth of the trials supporting approval of drugs to treat solid tumors, INV was the only method used to assess ORR. For consistency, and the ability to make relative cross-trial comparisons of ORR between agents, BICR should be considered for evaluation of tumor response in all registrational trials.

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A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma

Cancers ◽

10.3390/cancers12082270 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2270

Author(s):

Merve Hasanov ◽

Matthew J. Rioth ◽

Kari Kendra ◽

Leonel Hernandez-Aya ◽

Richard W. Joseph ◽

...

Keyword(s):

Overall Survival ◽

Uveal Melanoma ◽

Phase Ii ◽

Stable Disease ◽

Objective Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Objective Response ◽

Progression Free Survival ◽

Free Survival

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5–5.6), and the median overall survival was 11.9 months (95% CI 9.0–16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

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Final analysis of a multicenter, randomized phase II trial comparing three different chemoradiotherapy regimens in the treatment of patients with locally advanced, nonmetastatic pancreatic cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4610 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4610-4610

Author(s):

R. Wilkowski ◽

S. Boeck ◽

S. Ostermaier ◽

R. Sauer ◽

M. Herbst ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Trial ◽

Objective Response ◽

Locally Advanced ◽

Study Endpoint ◽

Hematological Toxicity ◽

Primary Study ◽

Grade 3

4610 Background: To date, no standard treatment approach for patients (pts) with non-resectable, locally advanced pancreatic cancer (PC) is defined. Methods: Within a prospective phase II trial treatment-naive pts with locally advanced PC and adequate organ function were randomly assigned to three different CRT regimens; all pts received a conventionally fractionated radiotherapy of 50 Gy (with a daily dose of 2.0 Gy) and were randomized to either concurrent 5-FU as a 24h-infusion (350 mg/m2/d on each day of radiotherapy, RT-5FU arm), concurrent low-dose gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 on days 1, 8, 22, and 29 (RT-GC arm), or the same concurrent treatment followed by a sequential chemotherapy with full- dose gemcitabine (1000 mg/m2) and cisplatin (50 mg/m2) every two weeks (RT-GC+GC arm). Treatment duration in the RT- GC+GC arm was upon disease progression or unacceptable toxicity. The primary study endpoint was the overall survival (OS) rate after 9 months (mo); secondary endpoints included response rate (WHO criteria), progression-free survival (PFS), resectability and toxicity. Results: Ninety-five patients (median age 64 years, 54% male, 50% KPS 90–100%) were recruited from 12 German centers. Seventy patients were evaluable for objective response: the intent-to-treat response rate (CR+PR) was 19% in the RT-5FU arm, 22% in the RT-GC arm and 13% in the RT-GC+GC arm, respectively. Overall, 18 pts (19%) underwent surgical resection after initial CRT (R0 in 8 pts). After a median follow-up of 8.6 mo, median PFS was estimated with 4 mo (RT-5FU), 5.6 mo (RT-GC) and 6 mo (RT- GC+GC), respectively (p=0.21). The corresponding median OS times were 9.6 mo, 9.3 mo and 7.3 mo (p=0.61). Hematological grade 3/4 toxicities were higher in the two gemcitabine/cisplatin-containing arms, but no grade 3/4 febrile neutopenia was observed. Regarding non-hematological toxicity, nausea/vomiting were more frequently in the RT-GC and RT-GC+GC arm, whereas diarrhea was more frequent in the RT-5FU arm. Conclusions: Based on these data, gemcitabine/cisplatin-based CRT does not achieve a higher clinical efficacy compared to RT-5FU, and is associated with increased hematological toxicity. [Table: see text]

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A phase II trial of first-line FOLFIRINOX for patients with advanced gastroesophageal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.89 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 89-89 ◽

Cited By ~ 1

Author(s):

Haeseong Park ◽

Andrea Wang-Gillam ◽

Rama Suresh ◽

Caron E. Rigden ◽

Manik A. Amin ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Therapeutic Option ◽

Performance Status ◽

Gastroesophageal Junction ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

First Line ◽

Gastroesophageal Adenocarcinoma

89 Background: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). FOLFIRINOX has been used in first line therapy in other GI cancers (i.e pancreatic and CRC) with impressive efficacy signals. Methods: This is a phase II study of first line combination chemotherapy with fluorouracil (5-FU), irinotecan, and oxaliplatin in patients with advanced gastric, esophageal, or gastroesophageal junction adenocarcinoma (NCT01928290). Starting doses were 5-FU 400mg/m2 bolus followed by 2400 mg/m2 over 46 hours with leucovorin 400 mg/m2, irinotecan 180 mg/m2, and oxaliplatin 85 mg/m2. Trastuzumab was administered as 6 mg/kg loading dose then 4 mg/kg every 14 days if patients had HER2+ cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), time to progression (TTP), clinical benefit rate (CBR), and duration of response. Enrollment of 41 patients with HER2- disease was planned to reach one-sided = 0.10 and power 0.90 with goal of detecting true ORR60%. No enrollment goal was planned for HER2+. Results: From Nov 2013 to July 2017, 58 patients were enrolled, 25 out of 58 (43%) had HER2+ disease. Forty-nine patients were evaluable for response as they completed at least one restaging scan. ORR was 78% (38/49) in all patients, 67% (18/27) in HER2-, 91% (20/22) in HER2+. One patient (2%) had complete response, 37 (76%) had partial response, 7 (14%) had stable disease > 6 months; therefore, CBR was 92%. Median PFS is 11.9 months, median OS is 17.4 months and median follow up time 16.1 months. 41 (83.7%) had dose modification or delay during treatment. There were no unexpected toxicities. Conclusions: FOLFIRINOX with or without trastuzumab showed remarkable ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. Further investigation in larger population is warranted. Clinical trial information: NCT01928290.

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A randomized phase II/III study comparing carboplatin and irinotecan with carboplatin and etoposide for the treatment of elderly patients with extensive-disease small cell lung cancer (JCOG1201/TORG1528).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8571 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8571-8571

Author(s):

Tsuneo Shimokawa ◽

Yuki Misumi ◽

Hiroaki Okamoto ◽

Yukio Hosomi ◽

Isamu Okamoto ◽

...

Keyword(s):

Overall Survival ◽

Phase Ii ◽

Objective Response Rate ◽

Response Rate ◽

Objective Response ◽

Progression Free Survival ◽

Japanese Patients ◽

Significant Difference ◽

Elderly Japanese ◽

Elderly Japanese Patients

8571 Background: Carboplatin and etoposide is the current standard treatment for elderly extensive-disease small-cell lung cancer (ED-SCLC). The purpose of this study is to evaluate the efficacy and safety of carboplatin and irinotecan compared with carboplatin and etoposide in elderly Japanese patients with ED-SCLC in a randomized phase II/III design. Methods: Eligibility included histologically or cytologically proven SCLC, no previous systemic chemotherapy, performance status of 0 to 2, and aged 71 years or older. Patients received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on day 1 to 3) (CE) every 3 weeks for 4 cycles or carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on day 1 and 8) (CI) every 3 weeks for 4 cycles. In the phase II part, the primary endpoint was the objective response rate of the CI arm and the secondary endpoint was adverse events. In the phase III part, the primary endpoint was overall survival, and the secondary endpoints were progression-free survival, objective response rate, adverse events, and symptom score. This study was designed to confirm the superiority of CI arm in terms of overall survival over CE arm. The median survival time with CI arm was expected to be increased by 3.5 months with hazard ratio (HR) of 0.750 (10.5 vs. 14.0 months). The sample size was set at 250 to observe the required number of events of 227 with one-sided alpha level of 0.05, a power of 70%, an accrual period of 6.5 years, and a follow-up period of 1.5 years. Results: Between December 2013 and June 2019, 258 patients were randomized (CE arm, 129 patients; CI arm, 129 patients). The median age was 75 (range, 71-90). The characteristics of the patients were well balanced between CE arm and CI arm. Overall survival, progression-free survival, and objective response rate of CE arm vs. CI arm were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.848 (95% CI, 0.650-1.105)) (one-sided P=0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 months (95% CI, 4.5-5.2) (HR, 0.851 (95% CI, 0.664-1.090)) (two-sided P=0.21), and 59.7% (77 of 129) vs. 64.3% (83 of 129), respectively. Symptom score showed no significant difference between the arms. Higher incidences of myelosuppression of grade 3 or worse occurred with CE arm, whereas higher incidences of gastrointestinal toxicity of grade 3 or worse occurred with CI arm. Three treatment-related deaths including lung infection in CE arm and lung infection and sepsis in CI arm were observed. Conclusions: Efficacy tended to be favorable in carboplatin and irinotecan arm, but there was no statistically significant difference. These results indicate that carboplatin and etoposide is a still standard treatment in elderly Japanese patients with ED-SCLC. Clinical trial information: 000012605.

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Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002057 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002057

Author(s):

Yousef Zakharia ◽

Robert R McWilliams ◽

Olivier Rixe ◽

Joseph Drabick ◽

Montaser F Shaheen ◽

...

Keyword(s):

Phase Ii ◽

Single Agent ◽

Objective Response ◽

Progression Free Survival ◽

Standard Of Care ◽

Complete Response ◽

Advanced Melanoma ◽

Free Survival ◽

Programmed Death ◽

Evaluable Population

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

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Single-arm phase II study of low-dose paclitaxel and pembrolizumab in platinum-refractory metastatic urothelial carcinoma (UC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.433 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 433-433

Author(s):

Rhonda L. Bitting ◽

Donald Charles Vile ◽

Janet A. Tooze ◽

Christopher Y. Thomas ◽

Morgan Neve ◽

...

Keyword(s):

Phase Ii ◽

Low Dose ◽

Immune Cell ◽

Single Agent ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

Intention To Treat ◽

Definitive Therapy ◽

Platinum Refractory

433 Background: Single agent checkpoint inhibition is effective in a small proportion of platinum-refractory UC patients but improvements are needed. UC is highly inflammatory, and low-dose chemotherapy may enhance the response to immunotherapy. We evaluated whether combination therapy with low-dose paclitaxel and pembrolizumab is more efficacious than single-agent pembrolizumab which had an objective response rate (ORR) of 21% in a similar patient population in the KEYNOTE-045 study. We also incorporated multiple novel biomarker studies to explore immune regulatory mechanisms in UC. Methods: This is a prospective, single-arm phase II trial (NCT02581982) of pembrolizumab combined with low-dose paclitaxel in patients with platinum-refractory metastatic UC. Key inclusion criteria included measurable progression of disease within 12 months of platinum therapy and ECOG ≤1. Patients received pembrolizumab 200mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21 day cycle for up to 8 cycles unless clinical or radiographic disease progression or unacceptable adverse events (AEs) were observed. Responding patients could remain on pembrolizumab maintenance for up to 2 years. The primary endpoint was ORR; key secondary endpoints included overall survival (OS), 6-month progression free survival (PFS), and safety. Results: Twenty-seven patients were treated between 4/2016 - 6/2020, with a median follow up of 9.9 months. At baseline, the median age was 68 years (range 49-80), with 81% men and 78% non-Hispanic white. The majority (59%) were ECOG 1. Twenty-one of 27 (78%) received prior definitive therapy: chemoradiation in 24% and surgery in 76%. The majority (78%) of patients received prior cisplatin. 70% progressed on a cisplatin-based regimen while 30% progressed on carboplatin-based regimen within 12 months of study entry. The ORR by intention to treat was 9 of 27 patients (33%) and in patients evaluable for response by imaging was 9 of 25 (36%), including 3 with complete response. Disease control rate in evaluable patients was 72%. Six-month PFS was 46.8% (95% CI: 27.2%, 64.2%) and median OS was 11.7 months (95% CI: 8.7 mo, NR). Common ≥ grade 2 AEs were anemia (44%), lymphopenia (37%), hyperglycemia (33%), and fatigue (33%). Possible treatment-related at least grade 3 or 4 AEs occurred in 56% of subjects, including 2 immune-mediated AEs (pneumonitis and nephritis) resulting in therapy cessation but a durable partial response. There were no grade 5 events. Conclusions: This study illustrates that the addition of low-dose paclitaxel to pembrolizumab improves outcomes in patients with platinum-refractory UC, relative to single-agent pembrolizumab. No unanticipated safety signals emerged. Exploratory analyses including PDL1 status, tumor mutational burden, and change in circulating microRNAs and in immune cell populations are ongoing. Clinical trial information: NCT02581982.

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