Pancreatic Cancer
Conditions
Brief summary
Nimotuzumab is a humanized monoclonal antibody against epidermal growth factor receptor (EGFR). Clinical trials are ongoing globally to evaluate Nimotuzumab in different indications. Nimotuzumab has been approved to treat squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal carcinoma in different countries.The clinical phase Ⅲ trial designed to assess overall survival（OS）of the combination of Nimotuzumab administered concurrently with Gemcitabine in patients with RAS wild type of locally advanced or metastatic pancreatic cancer
Detailed description
Nimotuzumab is a humanized monoclonal antibody against epidermal growth factor receptor (EGFR). Clinical trials are ongoing globally to evaluate Nimotuzumab in different indications. Nimotuzumab has been approved to treat squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal carcinoma in different countries.The clinical phase Ⅲ trial designed to assess overall survival（OS）of the combination of Nimotuzumab administered concurrently with Gemcitabine in patients with RAS wild type of locally advanced or metastatic pancreatic cancer.Secondary objectives include time to progression（TTP）,progression-free survival（PFS）,Objective Response Rate（ORR）,Disease Control Rate（DCR）,Clinical Benefit Response（CBR）and safety.
Interventions
DRUGnimotuzumab
nimotuzumab,400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test.
DRUGGemcitabine
Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test.
OTHERPlacebo
Placebo，400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test.
Sponsors
NanJing PLA 81 Hospital
Fudan University
Biotech Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age:18-75 years old * KPS≥60 * Histological or cytological diagnosis that are unsuitable for radical radiotherapy or surgical treatment of locally advanced or metastatic pancreatic adenocarcinoma (≥6 months to the last adjuvant chemotherapy) * Has at least one objective measurable lesion can be evaluated according to Response Evaluation Criteria in Solid Tumors1.1(Helical CT examination of the longest diameter of target lesions≥10mm, such as lymph node metastasis only need the shortest path ≥15mm) * Life expectancy ≥12 weeks * K-RAS tumor tissue detected as the wild-type * Aspartate transaminase（AST）/aminotransferase（ALT）≤2.5×ULN，AST /ALT≤5×ULN（if liver metastases）；Total bilirubin≤2×ULN，Total bilirubin≤3×ULN（if liver metastases）；Absolute neutrophil count≥1.5×109/L；Blood platelet≥100×109/L；Hemoglobin≥90 g/L；Creatinine clearance≥60ml/min * Volunteered to participate this study, written informed consent and has a good compliance * Patients of childbearing age and their spouses are willing to take contraceptive measures
Exclusion criteria
* Before this study had received the following treatments：As a means of anti-tumor palliative chemotherapy and molecular targeted therapy.Target lesion had received radiotherapy without progression.within 4 weeks or be participating in clinical trials of other therapeutic/ interventionist clinical trial. * Undergone major surgery within 4 weeks. * The brain metastasis or leptomeningeal metastasis. * Has a history of malignancy other than the pancreatic cancer (except for the cured cervix in situ or basal cell carcinoma, and a five-year cure other cancers). * The merger has symptoms of ascites and requires clinical treatment. Accompanied by other serious disease, including but not limited:Congestive heart failure which is difficult to control (NYHA III or IV), Unstable angina, Poorly controlled arrhythmia, Uncontrolled moderate to severe hypertension(systolic blood pressure（SBP）\>160 mm Hg or diastolic blood pressure（DBP）\>100 mm Hg).Active infection.Diabetes which is difficult to control.Has mental illness which impacts the informed consent and / or compliance program.HIV infection.There is serious illness that other researchers consider is unsuitable to participate this study. * Known allergy to anti-EGFR antibody formulations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival（OS） | up to 3 years | The primary endpoint was overall survival (OS, defined as from randomization to death due to any cause). We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. The primary end point was evaluated in the full analysis set (FAS; all eligible patients who received at least one dose of nimotuzumab/placebo and had one evaluation of efficacy). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival（PFS） | up to 3 years | PFS, defined as from randomization to disease progression or all-cause death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Objective Response Rate（ORR） | Once every eight weeks，up to 5.4 months | Objective response rate (ORR), including complete response (CR) and partial response (PR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions. |
| Time to Progression（TTP） | up to 3 years | TTP, defined as from randomization to the first observation of disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Clinical Benefit Response（CBR） | every 8 weeks, up to 5.4 months | The clinical benefit response(CBR)was evaluated every 8 weeks on the basis of the Burris criteria. CBR included pain (intensity of pain and consumption of analgesics), PS (performance status, evaluated according to KPS) and weight changes. Effective is defined as at least one positive improvement in the CBR index (pain, physical status or weight change) and no negative indicator is found, which can be rated as a clinical benefit case. |
| Number of Participants With Adverse Events | up to 75.2 months | Adverse Events as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research. |
| Disease Control Rate（DCR） | Once every eight weeks，up to 5.4 months | Disease control rate (DCR), including complete response (CR) and partial response (PR) and stable disease(SD). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: CR, disappearance of all target lesions; PR, at least a 30% decrease in the sum of the longest diameter of target lesions. SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (PD, defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions). |
Countries
China
Participant flow
Recruitment details
We screened 480 patients between April 10, 2015, and September 2020, at 25 study sites in China. Finally, 90 patients with K-Ras gene wild-type were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Nimotuzumab- Gemcitabine Group receive nimotuzumab (400 mg, weekly) plus gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks) until disease progression or unacceptable toxicity. | 41 |
| Placebo-Gemcitabine Group receive Placebo plus gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks) until disease progression or unacceptable toxicity. | 41 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Withdrawal by Subject | 9 | 6 |
Baseline characteristics
| Characteristic | Nimotuzumab- Gemcitabine Group | Placebo-Gemcitabine Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 11 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 30 Participants | 63 Participants |
| Age, Continuous | 53 years | 57 years | 55 years |
| Diagnosis Locally advanced | 9 Participants | 8 Participants | 17 Participants |
| Diagnosis Metastatic | 32 Participants | 33 Participants | 65 Participants |
| Karnofsky performance-status score 60-80 score | 21 Participants | 19 Participants | 40 Participants |
| Karnofsky performance-status score 90-100 score | 20 Participants | 22 Participants | 42 Participants |
| Pancreatic tumor location Body | 6 Participants | 7 Participants | 13 Participants |
| Pancreatic tumor location Head | 17 Participants | 17 Participants | 34 Participants |
| Pancreatic tumor location Tail | 18 Participants | 17 Participants | 35 Participants |
| Race/Ethnicity, Customized Han | 41 Participants | 39 Participants | 80 Participants |
| Race/Ethnicity, Customized Others | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 14 Participants | 17 Participants | 31 Participants |
| Sex: Female, Male Male | 27 Participants | 24 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 36 / 45 | 40 / 45 |
| other Total, other adverse events | 44 / 45 | 44 / 45 |
| serious Total, serious adverse events | 15 / 45 | 5 / 45 |
Outcome results
Primary
Overall Survival（OS）
The primary endpoint was overall survival (OS, defined as from randomization to death due to any cause). We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. The primary end point was evaluated in the full analysis set (FAS; all eligible patients who received at least one dose of nimotuzumab/placebo and had one evaluation of efficacy).
Time frame: up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nimotuzumab- Gemcitabine Group | Overall Survival（OS） | 10.9 months |
| Placebo-Gemcitabine Group | Overall Survival（OS） | 8.5 months |
Secondary
Clinical Benefit Response（CBR）
The clinical benefit response(CBR)was evaluated every 8 weeks on the basis of the Burris criteria. CBR included pain (intensity of pain and consumption of analgesics), PS (performance status, evaluated according to KPS) and weight changes. Effective is defined as at least one positive improvement in the CBR index (pain, physical status or weight change) and no negative indicator is found, which can be rated as a clinical benefit case.
Time frame: every 8 weeks, up to 5.4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nimotuzumab- Gemcitabine Group | Clinical Benefit Response（CBR） | 11 Participants |
| Placebo-Gemcitabine Group | Clinical Benefit Response（CBR） | 10 Participants |
Secondary
Disease Control Rate（DCR）
Disease control rate (DCR), including complete response (CR) and partial response (PR) and stable disease(SD). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: CR, disappearance of all target lesions; PR, at least a 30% decrease in the sum of the longest diameter of target lesions. SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (PD, defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions).
Time frame: Once every eight weeks，up to 5.4 months
Population: We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. Secondary end points were analyzed only in the FAS.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nimotuzumab- Gemcitabine Group | Disease Control Rate（DCR） | 28 Participants |
| Placebo-Gemcitabine Group | Disease Control Rate（DCR） | 26 Participants |
Secondary
Number of Participants With Adverse Events
Adverse Events as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
Time frame: up to 75.2 months
Population: We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS (n=90).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nimotuzumab- Gemcitabine Group | Number of Participants With Adverse Events | Treatment-related Adverse Events | 31 participants |
| Nimotuzumab- Gemcitabine Group | Number of Participants With Adverse Events | Serious Adverse Events | 1 participants |
| Nimotuzumab- Gemcitabine Group | Number of Participants With Adverse Events | Drug reduction or discontinued for AE | 4 participants |
| Nimotuzumab- Gemcitabine Group | Number of Participants With Adverse Events | Withdrawal for AE | 2 participants |
| Nimotuzumab- Gemcitabine Group | Number of Participants With Adverse Events | All-Cause Mortality | 36 participants |
| Placebo-Gemcitabine Group | Number of Participants With Adverse Events | Drug reduction or discontinued for AE | 6 participants |
| Placebo-Gemcitabine Group | Number of Participants With Adverse Events | Treatment-related Adverse Events | 29 participants |
| Placebo-Gemcitabine Group | Number of Participants With Adverse Events | All-Cause Mortality | 40 participants |
| Placebo-Gemcitabine Group | Number of Participants With Adverse Events | Serious Adverse Events | 2 participants |
| Placebo-Gemcitabine Group | Number of Participants With Adverse Events | Withdrawal for AE | 1 participants |
Secondary
Objective Response Rate（ORR）
Objective response rate (ORR), including complete response (CR) and partial response (PR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions.
Time frame: Once every eight weeks，up to 5.4 months
Population: We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. Secondary end points were analyzed only in the FAS.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nimotuzumab- Gemcitabine Group | Objective Response Rate（ORR） | 3 Participants |
| Placebo-Gemcitabine Group | Objective Response Rate（ORR） | 4 Participants |
Secondary
Progression Free Survival（PFS）
PFS, defined as from randomization to disease progression or all-cause death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: up to 3 years
Population: We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. Secondary end points were analyzed only in the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nimotuzumab- Gemcitabine Group | Progression Free Survival（PFS） | 4.2 months |
| Placebo-Gemcitabine Group | Progression Free Survival（PFS） | 3.6 months |
Secondary
Time to Progression（TTP）
TTP, defined as from randomization to the first observation of disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: up to 3 years
Population: We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. Secondary end points were analyzed only in the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nimotuzumab- Gemcitabine Group | Time to Progression（TTP） | 4.7 months |
| Placebo-Gemcitabine Group | Time to Progression（TTP） | 3.7 months |