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Combination of CDDP at 75 mg/m2 (day 1) or CBDCA at Area Under the Curve=6 (AUC=6) (day 1) + PEM at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, CBDCA at AUC=6 (day 1) + nab-PTX at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no progression after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease progression or intolerable toxicity. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.

Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease progression or intolerable toxicity. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.

In patients with non-squamous histology, cisplatin (75 mg/m2) will be administered every 3 weeks until 4 cycles with pemetrexed and pembrolizumab.

Cis Platinum

In cisplatin-intolerable patients, carboplatin (AUC=6) will be administered every 3 weeks until 4 cycles with pemetrexed and pembrolizumab.

In patients with non-squamous histology, pemetrexed (500 mg/m2) will be administered every 3 weeks until progression or 2 years after initiation (35 cycles) with pembrolizumab.

In patients with squamous histology, nab-paclitaxel (100 mg/m2, day 1, 8, 15, tri-weekly) will be administered until 4 cycles with pembrolizumab.

nab paclitaxel

AKITO HATA, MD

Keisuke Tanigawa

Akito Hata

This is a phase II, multicenter, single-arm, non-blind study. To 21 patients with PD-L1 ≥50% locally advanced non-small cell lung cancer, the combination of Pembrolizumab and platinum-doublets will be intravenously administered without radiotherapy to evaluate the efficacy and safety of combination therapy with Pembrolizumab and platinum-doublets.

Trial procedure:

As induction therapy, ≤4 courses of combination therapy with Pembrolizumab at 200 mg (day 1) and a platinum preparation will be performed at 3-week intervals until disease exacerbation or intolerable toxicity appearance. Concerning combination therapy with a platinum preparation, the combination of cisplatin (CDDP) at 75 mg/m2 (day 1) or carboplatin (CBDCA) at Area Under the Curve=6 (AUC=6) (day 1) + pemetrexed (PEM) at 500 mg/m2 (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, carboplatin (CBDCA) at AUC=6 (day 1) + nanoparticle albumin-bound paclitaxel (nab-PTX) at 100 mg/m2 (days 1, 8, and 15) will be administered at 3-week intervals. If there is no exacerbation after the 4th course of induction therapy, it will be switched to maintenance therapy. For maintenance therapy, the combination of PEM at 500 mg/m2 (day 1) + Pembrolizumab at 200 mg (day 1) will be administered to patients with non-squamous cell carcinoma at 3-week intervals. To those with squamous cell carcinoma, Pembrolizumab at 200 mg (day 1) will be administered at 3-week intervals until disease exacerbation or intolerable toxicity appearance. Pembrolizumab administration should be continued for 2 years involving induction and maintenance therapies or until the 35th course.

In each patient, diagnostic imaging will be performed every 6 weeks (42 ± 7 days)(every 9 weeks after Week 18, every 12 weeks after Week 45) to evaluate tumor-reducing effects. Using images, the response rate (RR) and progression-free survival (PFS) will be evaluated based on the "Guidelines for evaluating the treatment response of solid cancer (RECIST 1.1)". It is possible to continue treatment until PD evaluated by the attending physician based on the RECIST 1.1, intolerable toxicity appearance, the appearance of concomitant diseases affecting the continuation of treatment, discontinuation based on the study investigator's evaluation, withdrawal, pregnancy, incompliance with investigational-drug administration or procedures described in the protocol, appearance of management-related reasons, or completion of Pembrolizumab administration for 2 years involving induction and maintenance therapies or the 35th course. Even after PD is definitively diagnosed by the study investigator based on the RECIST 1.1, it is possible to continue treatment if the patient's condition is stable and if treatment is considered to be advantageous for the patient by the study investigator. During the trial period, adverse events should be examined,and severity grading should be performed according to the CTCAE（NCI Common Terminology Criteria for Adverse Events）version 5.0.

In cases without any response at first radiographic evaluation (6 weeks), local salvage therapy using radiotherapy is recommended by a discretion of doctors in charge. At that timing, such cases are treated as a censored case.

After enrollment of 10 cases, the trial will be early terminated by confirmed PD according RECIST at their initial radiographic evaluation (6 weeks) more than 3 cases.

Background:

Lung cancer accounts for 13% of all cancer patients. In 2012, 1,800,000 persons were newly diagnosed with lung cancer. Internationally, the number of patients who died of lung cancer in 2012 reached 1,600,000. Lung cancer is the most frequent cause of cancer-related death in males and the second most frequent cause of cancer-related death in females. Non-small cell lung cancer accounts for approximately 85% of all lung cancer lesions.

Concerning the treatment of non-small cell lung cancer, tumorectomy is performed in a stage in which radical resection is possible, and cure may be achieved at a relatively high probability. When radical resection is impossible, therapeutic strategies differ between patients with locally advanced cancer and those with remote metastasis. Standard treatment for stage III (locally advanced stage in which radical resection is impossible) non-small cell lung cancer is chemoradiotherapy (CRT). In some patients, radical cure may be achieved, but severe irreversible toxicities, such as treatment-associated death, pneumonia, and esophageal stenosis, may appear. In two phase III clinical studies regarding CRT for stage III lung cancer in which radical resection is impossible in Japan (WJTOG0105 and Osaka Lung Cancer Study Group 0007 studies), treatment-associated death and grade ≥3 pneumonia were observed in 3/4% and 2/10%, respectively. A recent phase II comparative clinical study in Japan (WJOG5008L study) compared CDDP + S-1 therapy with CDDP + vinorelbine therapy, and indicated that the treatment-associated mortality rates and incidences of grade ≥3 pneumonia were7.4/9.3% and 9.3/7.4%, respectively.

The rate at which radical cure was achieved by CRT was estimated to be approximately 20% based on the results of previous phase III clinical studies. In these studies, the PFS curve after CRT reached a plateau after 2 years. Briefly, if there is no relapse \>2 years after treatment, the possibility of relapse-free survival may be high. This suggests that the 2-year PFS rate, which is also adopted as a primary endpoint in this study, is a surrogate marker of overall survival (OS).

Recently, the results of CRT in stage III patients in whom radical resection is impossible have not markedly improved, but it was demonstrated that additional immunotherapy after CRT prolonged the prognosis. A phase III comparative clinical study published in 2017 (PACIFIC study) indicated that the additional administration of a PD-L1 antibody, Durvalumab, to patients after CRT in stage III, in which radical resection is impossible, for 1 year prolonged the PFS (median: 16.8 vs. 5.6 months, respectively; HR 0.52; p\<0.0001) and OS (median: not reached vs. 28.7 months, respectively; HR 0.68; p=0.0025) in comparison with a placebo. Based on the results of the study, 1-year Durvalumab administration following CRT was established as standard treatment for stage III cancer, which is impossible to treat by radical resection.

However, in the above study, randomization was performed after CRT, and the subjects did not include those with PD during CRT, those with grade ≥2 pneumonia, those with a reduction in the performance status (PS), those in whom CRT could not be completed, or those in whom Durvalumab could not be introduced within 42 days after CRT; Durvalumab should be additionally administered to patients who completed CRT, but it is difficult to notice treatment options before CRT. Furthermore, the results of the PACIFIC study may have been obtained, excluding these patients with poor prognoses.

In patients with PD-L1 ≥50% stage IV non-small cell lung cancer, the marked therapeutic effects of monotherapy with Pembrolizumab have been reported. In a phase III comparative study (Keynote-024), monotherapy with Pembrolizumab significantly prolonged the PFS (median: 10.7 vs. 6.7 months, respectively; HR 0.50; p\<0.001) and OS (median: non-reached vs. non-reached, respectively; HR 0.60; p=0.005) in comparison with combination therapy with a platinum preparation, as primary treatment, in patients with PD-L1 ≥50% stage IV non-small cell lung cancer. Based on the results of the study, monotherapy with Pembrolizumab was established as primary standard treatment for PD-L1 ≥50% stage IV non-small cell lung cancer. In addition, a strategy to combine immunotherapy with chemotherapy was examined. A phase II comparative study involving patients with stage IV non-squamous, non-small cell lung cancer (Keynote-021 cohort G) showed that CBDCA + PEM + Pembrolizumab therapy prolonged the PFS (median: 19.0 vs. 8.9 months, respectively; HR 0.54; p=0.0067) and OS (median: non-reached vs. 20.9 months, respectively; HR 0.59; p=0.03) in comparison with CBDCA + PEM therapy. Interestingly, a population in which a plateau was reached after ≥24 months accounted for approximately 45% regardless of PD-L1. Furthermore, 16 of 20 PD-L1 ≥50% patients responded to treatment, with a response rate of 80%. Grades 3-5 adverse events occurred in 39.0% of the patients. There was a treatment-associated death (1.7%). To confirm the data, a phase III comparative study (Keynote-189) was conducted, supporting the efficacy of CBDCA + PEM + Pembrolizumab therapy. In the study, the response rate (61.4 vs. 22.9%, respectively), PFS (HR 0.36), and OS (HR 0.42) were significantly higher/longer in the 3-drug combination group (involving immunotherapy) among PD-L1 ≥50% patients. As the observation period was insufficient, it is difficult to evaluate the 2-year PFS and OS rates in the PD-L1 ≥50% patients, but the PFS and OS rates at 18 months were estimated to be approximately 40 and 70%, respectively, based on the survival curves. Concerning adverse events, the incidence of grade ≥3 toxicities and treatment-associated mortality rate in the 3-drug combination group were 67.2 and 6.7%, respectively, being slightly high. However, in the placebo group, the percentages were 65.8 and 5.9%, respectively; there were no differences. Furthermore, a phase III randomized controlled study of initial treatment for stage IV squamous cell carcinoma of the lung (Keynote-407) demonstrated the additive effects of pembrolizumab on combination therapy with a platinum preparation (CBDCA + nab-PTX). This therapy improved the response rate (58.4 vs. 38.0%, respectively), PFS (median: 6.4 vs. 4.8 months, respectively; HR 0.56; p\<0.001), and OS (median: 15.9 vs. 11.3 months, respectively; HR 0.64; p=0.008). As the observation period was insufficient, it is difficult to evaluate the 2-year PFS and OS rates. However, the PFS and OS rates at 15 months were estimated to be approximately 30 and 50%, respectively, based on the survival curves. The hazard ratios (HRs) of PFS and OS in PD-L1 ≥50% patients were 0.37 and 0.64, respectively. Furthermore, there was no difference in the incidence of serious adverse events (grade ≥3) (69.8 vs. 68.2%, respectively). These data suggest the potent therapeutic effects of chemotherapy + Pembrolizumab in both PD-L1 ≥50% non-squamous and squamous cell carcinoma patients.

With respect to the effects of immunotherapy in an earlier stage, the efficacy of nivolumab as stage II/III preoperative therapy was reported. According to this report, nivolumab administered twice before surgery led to a major pathologic response (MPR rate: the rate of viable cells, \<10%) in 9 (43%) of 21 patients. A higher MPR rate may be achieved by preoperative chemotherapy + immunotherapy. According to a report from the American Society of Clinical Oncology in 2018, the MPR rate after CBDCA + nab-PTX + Atezolizumab therapy (n=14), as stage II/III preoperative treatment, was 50%. In addition, at a meeting held by the World Conference on Lung Cancer in 2018, it was reported that pathological complete remission was achieved in 18 (60%) of 30 surgically treated patients after CBDCA + PTX + nivolumab therapy, and that an MPR was achieved in 6 (20%); the MPR rate was 80%. These data also suggest that immunotherapy is more effective in an earlier stage, and that the combination of chemotherapy and immunotherapy is much more effective. Considering that a durable response is achieved in most patients with complete or partial remission among stage IV patients, a durable response may be achieved at a high probability in stage III patients with an MPR after chemotherapy + immunotherapy. Furthermore, a study indicated that, among stage IV patients, PD-1 antibody therapy was more effective in those with a smaller tumor volume. In stage III patients, there is no remote metastasis, and the tumor volume may be smaller than in stage IV patients. Therefore, considering a high MPR rate after stage II/III preoperative therapy and a more favorable patient status with a small tumor volume and a small number of metastatic organs in stage III patients, chemotherapy + immunotherapy may be more effective than chemotherapy + Pembrolizumab in stage IV patients.

Based on the above background, we hypothesized that Pembrolizumab + chemotherapy might exhibit sufficient therapeutic effects similar to those of CRT in the absence of radiotherapy if PD-L1 is ≥50% in patients with non-resectable stage III non-small cell lung cancer. Furthermore, the toxicity of CRT can be avoided, and there may be a marked improvement in tolerability. Therefore, we designed a phase II, multicenter, cooperative, single-group, physician-guided trial of combination chemotherapy with Pembrolizumab and a platinum preparation in the absence of radiotherapy involving PD-L1 ≥50% stage III locally advanced non-small cell lung cancer.

Pembrolizumab + Platinum Doublets Without Radiation for Programmed Death-ligand 1 (PD-L1) ≥50% Locally Advanced NSCLC

Pembrolizumab + Platinum Doublets Without Radiation for Patients With PD-L1 ≥50% Locally Advanced Non-small Cell Lung Cancer: a Multicenter Prospective Single Arm Phase II Study

Differences of Response rate in percent according to PD-L1 Total Proportion Score in percent

Differences of Progression-free survival in months according to PD-L1 Total Proportion Score in percent

Differences of Overall survival in months according to PD-L1 Total Proportion Score in percent

Number of non-progression cases/all enrolled cases at 2 years

Analysis of grade and incidence of adverse events

Merck Sharp & Dohme LLC

Kobe Minimally Invasive Cancer Center

Akito Hata, Director of Division of Thoracic Oncology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Small Cell Lung Carcinoma

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Neuroendocrine Tumors

Carcinoma, Small Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Small Cell Lung Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Neuroendocrine Tumor

Neuroepithelioma

Irinotecan

Etoposide

Gemcitabine

Vinorelbine

Doxorubicin

Liposomal doxorubicin

Etoposide phosphate

Taxane

Antimetabolites

Topoisomerase I Inhibitors

RRx-001 weekly for 3 weeks followed by up to 4 cycles of carboplatin or cisplatin plus etoposide and then RRx-001 and carboplatin or cisplatin (for patients with stable disease (SD) or better at discontinuation of platinum).

Carboplatin or cisplatin plus etoposide or irinotecan or vinorelbine until progression or intolerable toxicity

RRx-001 weekly for 3 weeks followed by up to 6 cycles of cisplatin or carboplatin plus paclitaxel or nab-paclitaxel or pemetrexed and then RRx-001 maintenance (for patients with stable disease or better at discontinuation of platinum).

RRx-001 weekly until progression followed by up to 6 cycles of carboplatin or cisplatin plus etoposide and then RRx-001 maintenance (for patients with stable disease or better at discontinuation of platinum).

RRx-001 weekly for 2 weeks followed by 2 cycles of Carboplatin chemotherapy and then RRx-001/Carboplatin maintenance (for patients with stable disease or better at discontinuation of platinum).

Carboplatin, Etoposide, Doxil, Gemcitabine or Vinorelbine or Taxane until progression or intolerable toxicity

RRx-001

Doxil

Nab-Paclitaxel

Bryan Oronsky, MD, PhD

This study is designed to explore the potential of the epigenetic agent RRx-001 to sensitize patients who previously received and now have failed a platinum based doublet regimen. RRx-001 is administered with autologous blood once weekly followed by or in combination with reintroduction of platinum-based doublet therapy.

This is an open label, four 'cohort' study for administration of RRx-001 with autologous blood once weekly followed by or in combination with reintroduction of platinum-based doublet therapy according to the treatment schedule listed below. Small cell carcinoma and ovarian cohort participants will be randomized to 1 of 2 treatment arms, respectively. Neuroendocrine and NSCLC patients will be enrolled to single arms.

Participants with SCC will receive one of the following; RRx-001 followed by platinum doublet chemotherapy or platinum based chemotherapy alone. HGNEC, RRx-001 followed by platinum doublet chemotherapy. NSCLC, RRx-001 followed by platinum doublet chemotherapy. Participants with Platinum Refractory/Resistant Ovarian and MMMT will receive one of the following, RRx-001 followed by platinum doublet chemotherapy or chemotherapy alone.

Approximately 213 participants will be enrolled.

RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)

A Phase II Study of RRx-001 in Platinum Refractory/Resistant Small Cell Carcinoma, EGFR TKI Resistant EGFR+ T790M Negative Non-Small Cell Lung Cancer, High Grade Neuroendocrine Tumors and Resistant/Refractory Ovarian Cancer Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)

the time from enrollment until the time of death from any cause or last follow-up. Patients will be followed clinically as outlined in the treatment schedule and will be followed off study for death.

The proportion of patients who achieve a reduction in the sum of target lesions by 30% following the re-administration of chemotherapy.

Radiographic assessment of disease burden will be evaluated by CT and disease RR will be documented using RECIST v1.1.

The percentage of patients who have achieved complete response, partial response and stable disease (as per RECIST v1.1).

the time from enrollment to the time of the first radiographic documentation of objective progression as defined by RECIST v1.1 or death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab + Platinum Doublets Without Radiation for Programmed Death-ligand 1 (PD-L1) ≥50% Locally Advanced NSCLC	NCT04153734	Locally Advance...	Pembrolizumab Cis Platinum Carboplatin Pemetrexed nab paclitaxel	-	Kobe Minimally Invasive Cancer Center
Pembrolizumab + Platinum Doublets Without Radiation for Programmed Death-ligand 1 (PD-L1) ≥50% Locally Advanced NSCLC	NCT04153734	Locally Advance...	Pembrolizumab Cis Platinum Carboplatin Pemetrexed nab paclitaxel	-	Kobe Minimally Invasive Cancer Center
RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)	NCT02489903	Small Cell Carc... Carcinoma, Non-... Neuroendocrine ... Ovarian Epithel...	RRx-001 Cisplatin Etoposide Carboplatin Irinotecan Vinorelbine Doxil Gemcitabine Taxane Paclitaxel Nab-Paclitaxel Pemetrexed	18 Years -	EpicentRx, Inc.

Spots Global Cancer Trial Database for platinum doublets