UMIN-CTR Clinical Trial

Public title

A phase III study comparing nivolumab with nivolumab plus docetaxel in patients with previously treated advanced non-small-cell lung cancer: a randomized phase II/III trial(TORG1630)

Acronym

NIV vs NIV+DTX Phase II/III (CONDUCT study)

Scientific Title

A phase III study comparing nivolumab with nivolumab plus docetaxel in patients with previously treated advanced non-small-cell lung cancer: a randomized phase II/III trial(TORG1630)

Scientific Title:Acronym

NIV vs NIV+DTX Phase II/III (CONDUCT study)

Region

Japan

Condition

Lung cancer

Classification by specialty

Pneumology

Hematology and clinical oncology

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

To investigate whether the combination of nivolumab plus docetaxel will improve overall survival compared with nivolumab monotherapy in previously treated non-small cell lung cancer.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Phase II,III

Primary outcomes

Phase II: 6 months PFS, Grade 3 =< pneumonitis rate(within 12 weeks)
Phase III: Overall survival, Safety

Key secondary outcomes

Phase II: Response rate
Phase III: Progression-free survival, Objective response rate, Safety

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -no one is blinded

Control

Active

Stratification

YES

Dynamic allocation

YES

Institution consideration

Institution is not considered as adjustment factor.

Blocking

NO

Concealment

Central registration

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Nivolumab

Interventions/Control_2

Nivolumab plus docetaxel

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

1.Histologically or cytologically confirmed NSCLC.
2.Previously treated, at least one regimen cytotoxic chemotherapy, and stage III or IV or post operation recurrence.
3.Less than 2 regimen previous chemotherapy. EGFR-TKI and ALK-TKI are not regarded as regimen.
4.Aged 20 years or older.
5.ECOG performance status 0 to 1.
6.Written informed consent.

Key exclusion criteria

1.Previously treated by docetaxel.
2.Previously treated by antibody targeting to PD-1, PD-L1, PD-L2, CD137, or CTLA-4.
4.Synchronous or metachronous (within 5 years) malignancies, except for carcinoma in situ or mucosal tumors curatively treated with local therapy.
5.Active CNS metastasis or meningitis carcinomatous. (If patients were received brain radiation, and stable clinically, it is eligible.)
6.Evident interstitial pneumonia in CT.

Target sample size

350

Name of lead principal investigator

1st name	Hiroaki
Middle name
Last name	Okamoto

Organization

Yokohama Municipal Citizen's Hospital

Division name

Medical Oncology/ Respiratory Medicine

Zip code

221-0855

Address

1-1-1 Mitsuzawa-Nishi-machi, Kanagawa-ku, Yokohama-shi, Kanagawa

TEL

045-316-4580

Email

hi01-okamoto@hosp.city.yokohama.lg.jp

Name of contact person

1st name	Tsuneo
Middle name
Last name	Shimokawa

Organization

Yokohama Municipal Citizen's Hospital

Division name

Respiratory Medicine

Zip code

221-0855

Address

1-1-1 Mitsuzawa-Nishi-machi, Kanagawa-ku, Yokohama-shi, Kanagawa

TEL

045-316-4580

Homepage URL

Email

ts00-shimokawa@hosp.city.yokohama.lg.jp

Institute

Thoracic Oncology Research Group

Institute

Department

Personal name

Organization

Ono Pharmaceutical Co. Ltd
Bristol-Myers Squib K.K.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

National Cancer Center Hospital East Certified Review Board

Address

6-5-1, Kashiwanoha, Kashiwa, Chiba

Tel

04-7133-1111

Email

ncche-irb@east.ncc.go.jp

Secondary IDs

YES

Study ID_1

jRCTs031180331

Org. issuing International ID_1

jRCT

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2016

Year

05

Month

01

Day

URL releasing protocol

-

Publication of results

Published

URL related to results and publications

https://doi.org/10.1158/1078-0432.CCR-22-1687

Number of participants that the trial has enrolled

131

Results

One hundred twenty-eight patients (each arm, n=64) were included in the full analysis set (FAS). Overall survival was evaluated as the primary endpoint. The median survival time and its 95% CI were 14.7 months [11.4, 18.7] in the standard treatment group A and 23.1 months [16.7, -] in the study treatment B group, and group B significantly improved overall survival compared with group A (p = 0.0310, one sided). Hematotoxicity and gastrointestinal adverse events were more common in arm B than in arm A.

Results date posted

2022

Year

08

Month

30

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

In Phase II, of the 100 patients enrolled, 50 patients were assigned to Group A and 50 patients to Group B. Of these, there was one treatment-naive patient in Group A and one treatment-naive patient in Group B.
In Phase III, of the 131 patients enrolled, 66 patients were assigned to the standard treatment group A (hereinafter referred to as Group A) and 65 patients to study treatment group B (hereinafter referred to as "Group B"). Of these, one treatment-naive patient and one ineligible patient were in Group A, and one treatment-naive patient was in Group B.
Assignment adjustment factors and other factors were as follows;
- PS (0 vs. 1): PS (0) was observed in 22 patients (34.4%) in Group A and in 21 patients (32.8%) in Group B. PS (1) was observed in 42 patients (65.6%) in Group A and in 43 patients (67.2%) in Group B.
- Histological type (squamous cell carcinoma vs. non-squamous cell carcinoma): Squamous cell carcinoma was observed in 14 patients (21.9%) in Group A and in 12 patients (18.8%) in Group B. Non-squamous cell carcinoma was observed in 50 patients (78.1%) in Group A and in 52 patients (81.3%) in Group B.
- Sex (male vs. female): There were 44 male patients (68.8%) in Group A and 45 male patients (70.3%) in Group B. There were 20 female patients (31.3%) in Group A and 19 female patients (29.7%) in Group B.
- EGFR gene mutation or ALK gene translocation (absence vs. presence vs. unknown): Absence was observed in 41 patients (64.1%) in Group A and in 41 patients (64.1%) in Group B. Presence was observed in 14 patients (21.9%) in Group A and in 13 patients (20.3%) in Group B. Unknown was observed in nine patients (14.1%) in Group A and in 10 patients (15.6%) in Group B.
- Clinical stage (stage IIIB, stage IIIC, stage IV, postoperative recurrence): Stage IIIB was observed in five patients (7.8%) in Group A and in two patients (3.1%) in Group B. Stage IIIC was not observed in any patients in either Group A or Group B. Stage IVA was observed in 29 patients (45.3%) in Group A and in 29 patients (45.3%) in Group B. Stage IVB was observed in 30 patients (46.9%) in Group A and in 33 patients (51.6%) in Group B.
- Number of prior chemotherapy regimens (1, 2): Regimen (1) was observed in 57 patients (89.1%) in Group A and in 58 patients (90.6%) in Group B. Regimen (2) was observed in seven patients (10.9%) in Group A and in six patients (9.4%) in Group B.
- Smoking history (absence, presence): Absence was observed in 15 patients (23.4%) in Group A, and in 12 patients (18.8%) in Group B. Presence was observed in 49 patients (76.6%) in Group A, and in 52 patients (81.3%) in Group B.
- PD-L1 (28-8) expression rate (three categories: 0, 1-49, and >= 50%): 28 patients (43.8%) in Group A and 23 patients (35.9%) in Group B were measurable. By expression rate category, the rate was 0% in 12 patients (42.9%) in Group A and in 10 patients (43.5%) in Group B. The rate was between 1% and 49% in 13 patients (46.4%) in Group A and in 10 patients (43.5%) in Group B. The rate was >= 50% in three patients (10.7%) in Group A and in two patients (8.7%) in Group B. No patients in Group A and one patient (4.3%) in Group B were indeterminable.

Participant flow

Of the 131 patients enrolled, 66 patients were assigned to standard treatment group A (hereinafter referred to as Group A) and 65 patients to study treatment group B (hereinafter referred to as Group B). Of these, one treatment-naive and one ineligible patient were excluded from Group A, and one treatment-naive patient was excluded from Group B, therefore FAS was 64 patients in Group A and 64 patients in Group B.
As part of the safety analysis, the number of protocol treatment courses was calculated for all treated patients. The median number of the previous courses was 2.0 in Group A and 4.0 in Group B. The minimum and maximum values were one course and 28 courses in Group A, one course and 31 courses in Group B, respectively.
Sixty of 64 FAS patients in Group A and 62 of 64 FAS patients in Group B discontinued the study treatment. The most common reason for discontinuation was failure of protocol treatment in both Groups A and B [46 patients (71.9%) in Group A and 33 patients (51.6%) in Group B]. The next most common reason was patient preference (not related to adverse events) in seven patients (10.9%) in Group A, and unable to continue protocol treatment due to adverse events in 25 patients (39.1%) in Group B.

Adverse events

Phase II part:
- The primary endpoint of the incidence of Grade >= 3 pneumonitis (within 12 weeks) and its 80% confidence interval (CI) were 12.2% (6.6, 20.5) in standard treatment group A (hereinafter referred to as Group A) and 12.2% (6.6, 20.5) in study treatment group B (hereinafter referred to as Group B). At the time of the interim analysis, there was 1 case of Grade 3 or higher pulmonary inflammation in Group A (N=49), and 5 cases were treated as "yes" because they had not yet reached 12 weeks from enrollment; in Group B (N=49), there were 0 cases of Grade 3 or higher pulmonary inflammation, and 6 cases were treated as "yes" because they had not reached 12 weeks from enrollment.
- The incidence of adverse events was evaluated as the secondary endpoint, and adverse events of Grade 3 or higher are listed below in order of frequency in each group.
In Group A, hypoalbuminemia occurred in two patients (4.2%) and other events that occurred in one patient were increased aspartate aminotransferase, hypokalemia, hypercalcemia, hyperglycemia, and anorexia.
In Group B, decreased neutrophil count occurred in 39 patients (79.6%), decreased white blood cell count in 32 patients (65.3%), febrile neutropenia in 10 patients (20.4%), and anemia in six patients (12.2%). Events that occurred in three patients (6.1%) were increased aspartate aminotransferase and hyperglycemia; events that occurred in two patients (4.1%) were hypoalbuminemia, hyponatremia, fatigue, and rash; and events that occurred in one patient (2.0%) were decreased platelet count, increased alanine aminotransferase, pyrexia, nausea, anorexia, and lung infection.
Phase III part:
- The incidence of adverse events was evaluated as the secondary endpoint. In Group A, common events included hypoalbuminemia in 33 patients (50.8%), malaise in 20 patients (30.8%), anemia in 17 patients (26.2%), and increased creatinine in 17 patients (26.2%). In Group B, hematologic toxicity such as decreased neutrophil count in 60 patients (93.8%), decreased white blood cell count in 57 patients (89.1%), and anemia in 46 patients (71.9%) occurred, and hypoalbuminemia occurred in 43 patients (67.2%), malaise in 37 patients (57.8%), and anorexia in 31 patients (48.4%).
- Particularly serious adverse events of Grade 5 included pneumonitis [one event (1.5%)] in Group A and myocarditis [one event (1.6%)] in Group B. Events of Grade 4 included endophthalmitis [one event (1.5%)], sepsis [one event (1.5%)], increased CPK [one event (1.5%)], recurrent non-small-cell lung cancer [one event (1.5%)], intracranial tumor hemorrhage [one event (1.5%)], and stroke [one event (1.5%)] in Group A, and recurrent non-small-cell lung cancer [two events (3.1%)], myasthenia gravis [one event (1.6%)], and impaired liver function [one event (1.6%)] in Group B.
Among serious adverse events (urgently reported), Grade 3 or higher pulmonary inflammation occurred in 2 patients (3.1%) in Group A and 2 patients (3.1%) in Group B.
- The main immune-related adverse reactions were as follows;
Adverse reactions in Group A included pneumonitis in eight patients (12.3%), malaise in seven patients (10.8%), increased aspartate aminotransferase in five patients (7.7%), and other events that occurred in four patients (6.2%) were diarrhea, pyrexia, increased alanine aminotransferase, increased creatinine, and anorexia.
Adverse reactions in Group B included malaise in 17 patients (26.6%). Events that occurred in 10 patients (15.6%) were increased aspartate aminotransferase and increased alanine aminotransferase; an event that occurred in nine patients (14.1%) was anorexia; events that occurred in eight patients (12.5%) were hypoalbuminemia and pneumonitis; events that occurred in six patients (9.4%) were increased creatinine and maculo-papular rash; events that occurred in five patients (7.8%) were pyrexia, fatigue, hyponatremia, and acneiform rash; and events that occurred in four patients (6.3%) were diarrhea and oral mucositis.

Outcome measures

Phase II part:
- Six-month progression-free survival rate was evaluated as the primary endpoint. The number of events was 29 in Group A and 16 in Group B. The 6-month progression-free survival rate and its 80% CI were 22.4% [13.2, 33.2)] in Group A and 64.4% [53.4, 73.5] in Group B, respectively.
- Response rate was evaluated as the secondary endpoint. The number, proportion, and its 95% CI of patients with a best overall response of either complete response (CR) or partial response (PR) were five patients in Group A (10.2% [3.4, 22.2]) and 12 patients in Group B (24.5% [13.3, 38.9]).
Phase III part:
- Overall survival was evaluated as the primary endpoint. The number of events was 42 (65.6%) in Group A and 33 (51.6%) in Group B. The median survival and its 95% CI were 14.7 months [11.4, 18.7] in Group A and 23.1 months [16.7, -] in Group B. Twelve-month survival rate and its 95% CI were 58.6% [45.1, 69.8] in Group A, 71.4% [58.5, 80.9] in Group B, and 24-month survival rate and its 95% CI were 32.9% [21.1, 45.3] in Group A and 47.7% [34.3, 60.0] in Group B. For the stratified log-rank test, the difference was statistically significant (p = 0.0310) at the 5% significance level of alpha (one sided). Using the stratified Cox regression model, the adjusted hazard ratio of Group B against Group A and its 90% CI were 0.63 [0.42, 0.95]. Therefore, study treatment B significantly improved overall survival compared with standard treatment A.
- The subgroup analysis of overall survival was conducted as the exploratory analysis of the primary endpoint. The subgroup factors were histological type (squamous cell carcinoma, non-squamous cell carcinoma), PS (0, 1), clinical stage (stage IIIB, stage IV, postoperative recurrence), sex (male, female), EGFR gene mutation or ALK gene translocation (absence, presence), number of prior chemotherapy regimens (1, 2), smoking history (absence, presence), and PD-L1 (28-8) expression rate (three categories: 0, 1-49, and >= 50%). In the subgroup analysis, study treatment B also significantly improved overall survival compared with standard treatment A, except for the number of prior chemotherapy regimens (2) and PD-L1 (28-8) expression rate (>= 50%), where the number of patients was small. There appeared to be no interaction between subgroup factor.
- Progression-free survival was evaluated as the secondary endpoint. The number of events was 54 (84.4%) in Group A and 55 (85.9%) in Group B. The median progression-free survival and its 95% CI were 3.1 months [2.0, 3.9] in Group A and 6.7 months [3.8, 9.4] in Group B. Six-month progression-free survival rate and its 95% CI were 26.4% [16.0, 37.9] in Group A, 56.3% [43.3, 67.4] in Group B, Twelve-month progression-free survival rate and its 95% CI were 15.8% [7.9, 26.3] in Group A and 22.6% [13.2, 33.5] in Group B, and 24-month progression-free survival rate and its 95% CI were 12.1% [5.2, 22.0] in Group A and 15.4% [7.6, 25.7] in Group B. For the stratified log-rank test, the difference was statistically significant (p = 0.0095) at the 5% significance level of alpha (two sided). Using the stratified Cox regression model, the adjusted hazard ratio of Group B against Group A and its 95% CI were 0.58 [0.39, 0.88]. Therefore, study treatment B significantly improved progression-free survival compared with standard treatment A.
- Response rate was evaluated as the secondary endpoint. Regarding the best overall response, CR was not observed in any patients in Group A and in one patient (1.8%) in Group B, PR was observed in eight patients in Group A (14.0%) and in 22 patients in Group B (40.0%), and the response rate and its 95% CI were eight patients in Group A (14.0%, 95% CI [6.3, 25.8]) and 23 patients in Group B (41.8%, 95% CI [28.7, 55.9]). The Fisher's exact test for the response rate was p = 0.0014, indicating a statistically significant difference. Therefore, study treatment B significantly improved the response rate compared with standard treatment A.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2017

Year

01

Month

21

Day

Date of IRB

2017

Year

08

Month

29

Day

Anticipated trial start date

2017

Year

11

Month

11

Day

Last follow-up date

2021

Year

06

Month

30

Day

Date of closure to data entry

2021

Year

08

Month

31

Day

Date trial data considered complete

2021

Year

09

Month

30

Day

Date analysis concluded

2021

Year

11

Month

30

Day

Other related information

Registered date

2016

Year

04

Month

07

Day

Last modified on

2022

Year

09

Month

02

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024452