Phase 2 Trial of Nivolumab, an Anti-PD-1 Monoclonal Antibody, as a Novel Neoadjuvant Pre-surgical Therapy for Locally Advanced Oral Cavity Cancer

SUMMARYBackgroundPembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate.MethodsNeoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10-49%), and pTR-2 (≥50%). Co-primary endpoints were pTR-2 among all patients, and one-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 expression and T-cell infiltration with pTR were assessed, and tumor clonal dynamics were evaluated. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov(NCT02296684), and is ongoing but closed to accrual.FindingsBetween June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR ≥10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-γ pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%).ConclusionsAmong patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical.FundingMerck, NCI, NIDCR, NHGRI and The V Foundation.

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Updated Results From a Phase 1/Randomized Phase 2 Trial of Response-Adapted Volume De-escalation (RAVD) for Locally Advanced Head and Neck Cancer

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2016.06.544 ◽

2016 ◽

Vol 96 (2) ◽

pp. S219

Author(s):

J.M. Melotek ◽

V.M. Villaflor ◽

T.G. Karrison ◽

R.J. Brisson ◽

E.A. Blair ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Phase 1 ◽

Locally Advanced ◽

Advanced Head ◽

Phase 2 ◽

Phase 2 Trial ◽

Randomized Phase 2

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Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial

The Lancet Oncology ◽

10.1016/s1470-2045(18)30143-8 ◽

2018 ◽

Vol 19 (5) ◽

pp. 639-648 ◽

Cited By ~ 33

Author(s):

Hans Gelderblom ◽

Claire Cropet ◽

Christine Chevreau ◽

Richard Boyle ◽

Martin Tattersall ◽

...

Keyword(s):

Locally Advanced ◽

Pigmented Villonodular Synovitis ◽

Villonodular Synovitis ◽

Phase 2 ◽

Open Label ◽

Phase 2 Trial ◽

Pigmented Villonodular

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Interim analysis of a phase II study of simultaneously integrated boost intensity modulated radiation therapy (SIB-IMRT) in combination with 5-FU and mitomycin-C among patients with locally advanced anal canal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15501-e15501

Author(s):

Carmen Florescu ◽

Justine Lequesne ◽

Jean-Michel Grellard ◽

Aurélie Parzy ◽

Marie-Pierre Galais ◽

...

Keyword(s):

Radiation Therapy ◽

Anal Canal ◽

Mitomycin C ◽

Interim Analysis ◽

Locally Advanced ◽

Intensity Modulated Radiation Therapy ◽

Phase 2 ◽

Efficacy And Safety ◽

Intensity Modulated ◽

Phase 2 Trial

e15501 Background: Concomitant radiochemotherapy is the standard treatment of locally advanced epidermoid anal canal carcinoma (EACC) but conventional radiotherapy (RT) frequently induces significant non-hematological toxicities, resulting in long treatment breaks. Given the numerous anatomic pelvic structures, EACC has become of interest for Intensity-Modulated Radiation Therapy (IMRT) despite the induced cutaneous toxicities responsible for RT breaks. Given the deleterious effect of treatment duration on local control and survival in other epidermoid cancers, continuous IMRT is challenging to control EACC. Several SIB-IMRT schedules provided similar results with moderate doses and schedules delivering higher doses with short breaks. Yet, standard SIB-IMRT schedule in EACC still not exists. We propose to concomitantly assess the safety and efficacy of continuous SIB-IMRT without planned breaks and concurrent chemotherapy (CT) to improve the treatment of locally advanced EACC by reducing the proportion of patients (pts) requiring RT breaks for toxicities. Methods: The CANAL-IMRT-01 phase 2 trial (NCT02701088) targets pts with histologically proven EACC candidate for concomitant RT of pelvic and inguinal nodes plus CT. Applying a two-step Bryant & Day design, the main criterion is based on both efficacy and safety. Efficacy is defined as the proportion of pts alive with no local disease progression 3 months after the end of IMRT; safety is defined as the proportion of pts with no RT breaks required by grade ≥3 toxicities. Assuming the unacceptable and acceptable proportions of pts without toxicity requiring IMRT break are 60 and 80% respectively, the unacceptable and acceptable 3-month-progression-free-survival are 80 and 90%, 14 assessable pts at first step and 46 in the second are required (alpha risk 5%, 90% power). To anticipate a 10% drop out rate, 16 pts were needed in first step, with ≥11 objective local responses and ≤6 toxicity-induced IMRT breaks to pursue. Treatment consists in 50 days of concomitant CT (2 cycles of 5FU and Mitomycin-C) and SIB-IMRT delivered by helical tomotherapy: 61.2Gy/1.7Gy to the primary tumor, 57.6Gy/1.6Gy to involved nodes, and 54/1.5Gy to elective pelvic lymph nodes. Results: From December 2015 to June 2017, 16 pts were enrolled: 11 female (73%), median age 62 [55-66]. 15 pts were assessable for efficacy and safety. All 15 pts had a 3-month locoregional response (12 complete responses, 3 partial responses). SIB-IMRT breaks were required by toxicities for 4 out of 15 pts: G1 radiodermitis, G2 inguinal and epithelitis, G1 fever, G3 anorexia and vertigo. Conclusions: The planned interim analysis of continuous SIB-IMRT plus CT allowed pursuing this phase 2 trial to assess the relevance of such schedule for locally advanced ASCC. Enrolment is still ongoing. Clinical trial information: NCT02701088.

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Single-Institute Clinical Experiences Using Whole-Field Simultaneous Integrated Boost (SIB) Intensity-Modulated Radiotherapy (IMRT) and Sequential IMRT in Postoperative Patients With Oral Cavity Cancer (OCC)

Cancer Control ◽

10.1177/1073274820904702 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107327482090470

Author(s):

Chen-Hsi Hsieh ◽

Pei-Wei Shueng ◽

Li-Ying Wang ◽

Li-Jen Liao ◽

Wu-Chia Lo ◽

...

Keyword(s):

Oral Cavity ◽

Oral Cavity Cancer ◽

Locally Advanced ◽

Intensity Modulated Radiotherapy ◽

Simultaneous Integrated Boost ◽

Clinical Experiences ◽

Risk Of Death ◽

Intensity Modulated ◽

Integrated Boost ◽

Sequential Technique

This study aimed to review clinical experiences using whole-field simultaneous integrated boost (SIB) intensity-modulated radiotherapy (IMRT) and sequential IMRT in postoperative patients with oral cavity cancer (OCC). From November 2006 to December 2014, a total of 182 postoperative patients with OCC who underwent either SIB-IMRT (n = 63) or sequential IMRT (n = 119) were enrolled retrospectively and matched randomly according to multiple risk factors by a computer. The differences were well balanced after patient matching ( P = .38). The median follow-up time was 65 months. For patients treated with the SIB technique and the sequential technique, the respective mortality rates were 36.8% and 20.0% ( P = .04). The primary recurrence rates were 26.3% and 10.0% ( P = .02), respectively. The respective marginal failure rates were 26.7% and 16.7%. A multivariate logistic regression analysis showed that patients who received the SIB technique had a 2.74 times higher risk of death than those who received the sequential technique (95% confidence interval = 1.10-6.79, P = .03). Sequential IMRT provided a significantly lower dose to the esophagus (5.2 Gy, P = .02) and trachea (4.6 Gy, P = .03) than SIB-IMRT. For patients with locally advanced OCC, postoperative sequential IMRT may overcome an unpredictable geographic miss, potentially with a lower marginal failure rate in the primary area. Patients treated by sequential IMRT show equal overall survival benefits to those treated by SIB-IMRT and a lower mortality rate than those treated by SIB-IMRT. Additionally, a reduced dose to the esophagus and trachea compared to sequential IMRT was noted.

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