Non-Small Cell Lung Cancer, NSCLC, Adenocarcinoma, Heregulin
Conditions
Keywords
NSCLC, Non-Small Cell Lung Cancer, heregulin, ErbB3, docetaxel
Brief summary
The purpose of this study is to determine whether the combination of MM-121 plus docetaxel is more effective than docetaxel alone in regards to PFS in patients with heregulin-positive NSCLC.
Detailed description
This study is a randomized, open-label, international, multi-center, phase 2 study in patients with Heregulin-positive NSCLC histologically classified as adenocarcinoma that have progressed following no more than two systemic therapies for locally advanced or metastatic disease, one of which must have been a platinum containing regimen. All patients will initially be screened for heregulin status. Eligible patients will be randomized to receive MM-121 in combination with docetaxel versus docetaxel alone.
Interventions
DRUGMM-121
Investigational, fully human antibody targeting and inhibiting ErbB3
DRUGDocetaxel
approved chemotherapy treatment for NSCLC
Sponsors
Merrimack Pharmaceuticals
Elevation Oncology
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, open-label, international, multi-center, Phase 2 study in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent * Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease * Tissue submitted for HRG-biomarker testing * ECOG performance status (PS) of 0 or 1
Exclusion criteria
* Known ALK mutation * Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene * Received \>2 prior systemic anti-cancer drug regimen for locally advanced disease * Prior treatment with an anti-ErbB3 antibody * CTCAE grade 3 or higher peripheral neuropathy * Symptomatic CNS metastases or CNS metastases requiring steroids * Any other active malignancy requiring systemic therapy * Clinically significant cardiac disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Randomization until progression of disease or death due to any cause within 3 years,11 months (the study terminated prematurely) | Progression Free Survival is defined as the time from randomization to the first documented radiographical progression of disease using RECIST v.1.1, or death from any cause, whichever came first based on investigator assessment. Patients that do not experience progression or death at the time of analysis were to be progression censored at the date of last valid tumor assessment. Progression-free survival time distribution and median survival for each treatment group were analyzed using the Kaplan-Meier method. Tumor response was evaluated by the local radiologist according to RECIST version 1.1 to establish disease progression by CT or MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Randomization through end of study up to 3 years, 11 months (the study terminated prematurely) | Objective Response Rate (ORR) is defined as the proportion of patients a best overall response characterised as either a Complete Response (CR) or Partial Response (PR), as defined according to RECIST v1.1 guidelines, relative to the total number of evaluable patients. Complete Response (CR) is defined as disappearance of all lesions and pathologic lymph nodes. Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions |
| Time to Progression | Randomization to date of objective tumor progression up to 3 years, 11 months (the study terminated prematurely) | Time to Progression (TTP) is defined as the time from the date of randomization to the date of objective tumor progression. In the actual analysis, duration of response (DOR) was analysed. |
| Overall Survival | From date of randomization until the date of death from any cause assessed upto 3 years,11 months (the study terminated prematurely) | Overall Survival (OS) is defined as the time from the date of randomization to the date of death from any cause |
| Pharmacokinetic (PK) Parameters of MM-121 in Combination With Docetaxel and Docetaxel When Given in Combination With MM-121. | The study terminated prematurely after 3 years, 11 months (02 Jan 2019). PK evaluation were to be performed on samples obtained at Week 1 pre-dose and post-dose and at pre-dose at Cycle 2 and beyond to assess pre-treatment through concentrations of MM-121 | Pharmacokinetic (PK) profile of MM-121 when given in combination with docetaxel, and of docetaxel when given in combination with MM-121. The maximum observed concentration (Cmax) were to be presented and calculated using non-compartmental analysis. Serum levels of MM-121 were to be measured at a central lab using an enzyme-linked immunosorbent assay. |
| Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | TEAEs were collected through the study completion (02 Jan 2019), up to 3 years, 11 months | Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration |
| Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | TEAEs were collected through the study completion (02 Jan 2019), up to 3 years, 11 months | Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration |
Countries
Canada, France, Germany, Hungary, Spain, United States
Participant flow
Recruitment details
87 multi-national sites
Pre-assignment details
One patient was inappropriately enrolled into the sherloc study hence why 152 and not 153
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Experimental): MM-121 in Combination With Docetaxel MM-121 (Seribantumab, a human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin-driven ErbB3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, seribantumab is designed to block ErbB3 signaling in order to enhance the anti-tumor effect of a combination therapy partner): 3000 mg fixed dose intravenous (IV) on Day 1 of each 21-day cycle
Docetaxel (approved chemotherapy treatment for non-small cell lung cancer (NSCLC)): 75 mg/m˄2 IV on Day 1 of each 21-day cycle | 103 |
| Arm B (Comparator): Docetaxel Alone Docetaxel (approved chemotherapy treatment for NSCLC):
75 mg/m˄2 IV on Day 1 of each 21-day cycle | 49 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 60 | 23 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Other | 5 | 4 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Progressive disease | 2 | 0 |
| Overall Study | Sponsor Decision | 28 | 12 |
| Overall Study | Withdrawal by Subject | 3 | 5 |
Baseline characteristics
| Characteristic | Arm B (Comparator): Docetaxel Alone | Arm A (Experimental): MM-121 in Combination With Docetaxel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 45 Participants | 63 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants | 58 Participants | 89 Participants |
| Age, Continuous | 62.8 years STANDARD_DEVIATION 7.28 | 62.6 years STANDARD_DEVIATION 10.07 | 62.8 years STANDARD_DEVIATION 8.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 90 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 11 Participants |
| Heregulin positive status and staining in archival tissue | 49 Participants | 103 Participants | 152 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) Stage IIA | 3 Participants | 5 Participants | 8 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) Stage IIB | 1 Participants | 1 Participants | 2 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) Stage IIIA | 4 Participants | 7 Participants | 11 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) Stage IIIB | 8 Participants | 13 Participants | 21 Participants |
| Metastatic burden (TNM Stage at Initial Diagnosis) Stage IV | 33 Participants | 77 Participants | 110 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 10 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 8 Participants | 15 Participants |
| Race (NIH/OMB) White | 38 Participants | 83 Participants | 121 Participants |
| Region of Enrollment Australia | 3 participants | 9 participants | 12 participants |
| Region of Enrollment Canada | 6 participants | 2 participants | 8 participants |
| Region of Enrollment France | 6 participants | 11 participants | 17 participants |
| Region of Enrollment Germany | 4 participants | 7 participants | 11 participants |
| Region of Enrollment Hungary | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Poland | 2 participants | 2 participants | 4 participants |
| Region of Enrollment South Korea | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Spain | 10 participants | 28 participants | 38 participants |
| Region of Enrollment Taiwan | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Thailand | 0 participants | 3 participants | 3 participants |
| Region of Enrollment United States | 15 participants | 38 participants | 54 participants |
| Sex: Female, Male Female | 19 Participants | 32 Participants | 51 Participants |
| Sex: Female, Male Male | 30 Participants | 71 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 64 / 103 | 25 / 49 |
| other Total, other adverse events | 103 / 103 | 47 / 49 |
| serious Total, serious adverse events | 40 / 103 | 15 / 49 |
Outcome results
Primary
Progression Free Survival
Progression Free Survival is defined as the time from randomization to the first documented radiographical progression of disease using RECIST v.1.1, or death from any cause, whichever came first based on investigator assessment. Patients that do not experience progression or death at the time of analysis were to be progression censored at the date of last valid tumor assessment. Progression-free survival time distribution and median survival for each treatment group were analyzed using the Kaplan-Meier method. Tumor response was evaluated by the local radiologist according to RECIST version 1.1 to establish disease progression by CT or MRI.
Time frame: Randomization until progression of disease or death due to any cause within 3 years,11 months (the study terminated prematurely)
Population: The Modified Intent-to-Treat (mITT) Population consisted of all randomized patients who received at least 1 dose of assigned therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Progression Free Survival | 3.4 months |
| Arm B (Comparator): Docetaxel Alone | Progression Free Survival | 4.1 months |
p-value: 0.230295% CI: [0.813, 2.35]Log Rank
Secondary
Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone
Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration
Time frame: TEAEs were collected through the study completion (02 Jan 2019), up to 3 years, 11 months
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | Patients with any TEAE-Related | 99 participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | Patients with any TEAE-Serious Adverse event | 40 participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | Patients with any NCI-CTCAE Grade 3 or Higher | 76 participants |
| Arm B (Comparator): Docetaxel Alone | Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | Patients with any TEAE-Related | 45 participants |
| Arm B (Comparator): Docetaxel Alone | Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | Patients with any TEAE-Serious Adverse event | 15 participants |
| Arm B (Comparator): Docetaxel Alone | Number of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | Patients with any NCI-CTCAE Grade 3 or Higher | 31 participants |
Secondary
Objective Response Rate
Objective Response Rate (ORR) is defined as the proportion of patients a best overall response characterised as either a Complete Response (CR) or Partial Response (PR), as defined according to RECIST v1.1 guidelines, relative to the total number of evaluable patients. Complete Response (CR) is defined as disappearance of all lesions and pathologic lymph nodes. Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions
Time frame: Randomization through end of study up to 3 years, 11 months (the study terminated prematurely)
Population: Modified Intent-to-Treat (ITT) population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Objective Response Rate | Objective Response | 14 Participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Objective Response Rate | Partial Response (PR) | 14 Participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Objective Response Rate | Stable Disease (SD) | 39 Participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Objective Response Rate | Progressive Disease | 12 Participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Objective Response Rate | Not Evaluable | 1 Participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Objective Response Rate | No Evaluation | 5 Participants |
| Arm B (Comparator): Docetaxel Alone | Objective Response Rate | Stable Disease (SD) | 26 Participants |
| Arm B (Comparator): Docetaxel Alone | Objective Response Rate | Objective Response | 2 Participants |
| Arm B (Comparator): Docetaxel Alone | Objective Response Rate | Not Evaluable | 1 Participants |
| Arm B (Comparator): Docetaxel Alone | Objective Response Rate | No Evaluation | 4 Participants |
| Arm B (Comparator): Docetaxel Alone | Objective Response Rate | Partial Response (PR) | 2 Participants |
| Arm B (Comparator): Docetaxel Alone | Objective Response Rate | Progressive Disease | 5 Participants |
p-value: 0.0455Cochran-Mantel-Haenszel
Secondary
Overall Survival
Overall Survival (OS) is defined as the time from the date of randomization to the date of death from any cause
Time frame: From date of randomization until the date of death from any cause assessed upto 3 years,11 months (the study terminated prematurely)
Population: Modified Intent-to-Treat (ITT) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Overall Survival | 7.7 months |
| Arm B (Comparator): Docetaxel Alone | Overall Survival | 8.4 months |
p-value: 0.543695% CI: [0.673, 2.122]Log Rank
Secondary
Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone
Treatment-emergent adverse events (TEAEs) are defined as any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration
Time frame: TEAEs were collected through the study completion (02 Jan 2019), up to 3 years, 11 months
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | TEAE-Related | 96.1 percentage of participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | TEAE-Serious Adverse event | 38.8 percentage of participants |
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | NCI-CTCAE Grade 3 or Higher | 73.8 percentage of participants |
| Arm B (Comparator): Docetaxel Alone | Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | TEAE-Related | 91.8 percentage of participants |
| Arm B (Comparator): Docetaxel Alone | Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | TEAE-Serious Adverse event | 30.6 percentage of participants |
| Arm B (Comparator): Docetaxel Alone | Percentage of Participants With Treatment-emergent Adverse Events Reported With the Combination of MM-121 With Docetaxel Versus Docetaxel Alone | NCI-CTCAE Grade 3 or Higher | 63.3 percentage of participants |
Secondary
Pharmacokinetic (PK) Parameters of MM-121 in Combination With Docetaxel and Docetaxel When Given in Combination With MM-121.
Pharmacokinetic (PK) profile of MM-121 when given in combination with docetaxel, and of docetaxel when given in combination with MM-121. The maximum observed concentration (Cmax) were to be presented and calculated using non-compartmental analysis. Serum levels of MM-121 were to be measured at a central lab using an enzyme-linked immunosorbent assay.
Time frame: The study terminated prematurely after 3 years, 11 months (02 Jan 2019). PK evaluation were to be performed on samples obtained at Week 1 pre-dose and post-dose and at pre-dose at Cycle 2 and beyond to assess pre-treatment through concentrations of MM-121
Population: The PK data were not collected for this abbreviated report. There was no pharmacokinetic data feasible for the analysis, and as such, no related analyses were performed. Hence, data could not be reported in the data table.
Secondary
Time to Progression
Time to Progression (TTP) is defined as the time from the date of randomization to the date of objective tumor progression. In the actual analysis, duration of response (DOR) was analysed.
Time frame: Randomization to date of objective tumor progression up to 3 years, 11 months (the study terminated prematurely)
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Experimental): MM-121 in Combination With Docetaxel | Time to Progression | 3.0 months |
| Arm B (Comparator): Docetaxel Alone | Time to Progression | NA months |
p-value: 0.2726Log Rank