Breast Cancer Metastatic
Conditions
Keywords
Bispecific Antibody immunoglobulin gamma-1(IgG1), Human Epidermal Growth Factor Receptor (HER)2, HER3, MCLA-128, Antibodies, bispecific, Immunologic Factors, Cytokines, combination Trastuzumab with and without Vinorelbine, zenocutuzumab
Brief summary
A Phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-128-based combinations. Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2. MCLA-128 (zenocutuzumab) is given in combinations in two metastatic breast cancer (MBC) populations, Human Epidermal Growth Factor Receptor (HER) 2-positive/amplified (Cohort 1) and Estrogen Receptor-positive/low HER2 expression (Cohort2). Two combinations treatments will be evaluated in Cohort 1, the doublet and triplet. Initially zenocutuzumab is given in combination with trastuzumab in the doublet. After the safety of the doublet has been assessed in 4-6 patients, MCLA-128 is given in combination with trastuzumab and vinorelbine in the triplet, in parallel to the efficacy expansion of the doublet. The doublet and triplet combinations are both evaluated in two steps with an initial safety run-in followed by a cohort efficacy expansion. In total up to 40 patients evaluable for efficacy are included in both the doublet and triplet. In Cohort 2 zenocutuzumab is administered in combination with the same previous endocrine therapy on which progressive disease is radiologically documented. A total of up to 40 patients evaluable for efficacy are included in the Cohort 2.
Detailed description
Study Design Phase 2, open-label, multicenter international study to evaluate the efficacy of MCLA-128 (zenocutuzumab)-based combinations in 2 metastatic breast cancer populations, Human Epidermal Growth Factor Receptor (HER)2-positive/amplified (Cohort 1) and estrogen receptor-positive/low-HER2 expression (Cohort 2). Three combination treatments were evaluated, 2 in Cohort 1 and 1 in Cohort 2. Cohort 1: To be eligible, patients had to have HER2-positive/amplified metastatic breast cancer, with confirmed HER2 overexpression by Immunohistochemistry (IHC) with a score of 3+ or of 2+ combined with positive Fluorescence in Situ Hybridization (FISH), have received up to 5 lines of HER2-directed therapy in the metastatic setting, and have progressed on the most recent line per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, and have been previously treated with trastuzumab, pertuzumab and an HER2 Antibody-Drug Conjugates (ADC) in any sequence and any setting. Initially zenocutuzumab was administered with trastuzumab (doublet combination). Safety was reviewed by an Independent Data Monitoring Committee (IDMC). If the safety of the doublet was approved, the triplet combination of zenocutuzumab plus trastuzumab and vinorelbine was to be evaluated in parallel with the doublet combination. The doublet and triplet Cohort 1 combinations were each evaluated in 2 steps with an initial safety run-in period in 4 to 6 patients who were reviewed by the IDMC before deciding to expand the cohort. The triplet combination go/no-go decision was made by the IDMC after evaluation of the doublet safety run-in patients (based on Adverse Avents \[AEs\], Serious Adverse Events \[SAEs\], relationship to study drug, and other clinically relevant parameters \[eg, laboratory parameters\], available pharmacokinetics, immunogenicity, and cytokine data). If the triplet combination was considered safe, the expansion of the doublet and triplet combinations was performed in parallel. Patients were included in the triplet or doublet in a 3:1 ratio, taking into account previous exposure to vinorelbine. After the safety run-in, if Cohort 1 doublet and Cohort 1 triplet combination therapies were considered tolerable by the IDMC, they were each to be expanded to a total of up to 40 patients evaluable for efficacy. If the doublet combination regimen was not well tolerated, Cohort 1 was to be closed. If the triplet combination was not well tolerated but the doublet was acceptable, the doublet expansion was to be continued. Cohort 2: To be eligible, patients had to have estrogen receptor-positive and low-HER2 expression metastatic breast cancer (IHC 1+, or IHC 2+ combined with negative FISH), and radiologic or photographic evidence of disease progression on the last line of prior endocrine therapy (administered for ≥12 weeks) that included an aromatase inhibitor (AI) or fulvestrant. Patients who had received up to 3 prior endocrine therapies in the metastatic setting and had progressed on a Cyclin-Dependent Kinase (CDK) inhibitor (in any line) were eligible. Zenocutuzumab was administered in combination with the same previous endocrine therapy on which progressive disease was radiologically/photographically documented. Up to 40 patients evaluable for efficacy were included.
Interventions
DRUGZenocutuzumab
full length immunoglobulin gamma-1 (IgG1) bispecific antibody targeting Human Epidermal Growth Factor Receptor (HER)2 and HER3
DRUGTrastuzumab
humanised IgG1 monoclonal antibody
DRUGVinorelbine
antineoplastic drug of vinca alkaloid family
DRUGEndocrine therapy
same endocrine therapy is administered as the last line of endocrine therapy
Sponsors
Merus N.V.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent before initiation of any study procedures. 2. Women with histologically or cytologically confirmed breast cancer with evidence of metastatic or locally advanced disease not amenable to any local therapy with curative intent: 2.1 Cohort 1 (zenocutuzumab + trastuzumab ± vinorelbine) 1. Documented Human Epidermal Growth Factor Receptor (HER)2 overexpression/amplification, defined as Immunohistochemistry (IHC) 3+ positive, or IHC 2+ combined with positive Fluorescence In Situ Hybridization (FISH), based on local analysis on the most recent tumor biopsy (preferably metastatic, otherwise primary), either fresh or archival collected within 24 months before screening. 2. Documented disease progression (by investigator assessment) on up to a maximum of 5 lines of HER2- directed therapy administered in the metastatic setting and progression on the most recent line. Trastuzumab, pertuzumab and an HER2 Antibody drug conjugates (ADC) (eg. Trastuzumab emtansine (T-DM1)) must have been previously administered in any sequence and in any setting. 2.2 Cohort 2 (zenocutuzumab + endocrine therapy) 1. Documented hormone receptor positive status (estrogen receptor positive and/or progesterone receptor positive), defined as ≥ 1% positive stained cells by local standards, based on local analysis on the most recent tumor biopsy. 2. Documented low-level HER2 expression, defined as IHC HER2 1+, or IHC HER2 2+ combined with negative FISH, based on local analysis on a fresh tumor biopsy or an archival biopsy collected within 24 months before screening (preferably metastatic, otherwise primary). 3. No more than 3 lines of prior endocrine therapy (aromatase inhibitor or fulvestrant) for metastatic disease, with radiologic or photographic evidence of disease progression on the last line, after at least 12 weeks of therapy. 4. Progression on a cyclin-dependent kinase inhibitor. 5. No more than 2 previous chemotherapy regimens for advanced/metastatic disease. Note: Pre/peri-menopausal women could be enrolled if amenable to be treated with the Luteinizing Hormone-Releasing Hormone (LHRH) agonist goserelin. Such patients must have commenced treatment with goserelin or an alternative LHRH agonist at least 4 weeks prior to study entry, and patients who received an alternative LHRH agonist prior to study entry must switch to goserelin for the duration of the trial. 3. At least one lesion with measurable disease as defined by Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1. For Cohort 2, patients with bone-only disease were eligible, even in the absence of measurable disease. Patients with bone-only disease must have lytic or mixed lesions (lytic + sclerotic), and imaging documenting progression on the last line of hormone therapy must be available for central review. 4. Age ≥ 18 years at signature of informed consent. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Life expectancy of ≥ 12 weeks, as per investigator. 7. Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA). 8. Adequate organ function: 1. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L. 2. Hemoglobin ≥ 9 g/dL. 3. Platelets ≥ 100 x 109/L. 4. Serum calcium within normal ranges (or corrected with supplements). 5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN (in cases of liver involvement, ALT/AST ≤5 x ULN and total bilirubin within normal ranges was allowed). 6. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥ 60 mL/min calculated according to the Cockcroft and Gault formula or Modification of Diet in Renal Disease (MDRD) formula for patients aged \>65 years (Protocol Appendix 19.2). 7. Serum albumin \>3.0 g/dL.
Exclusion criteria
1. Central nervous system metastases that are untreated or symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 14 days of study entry. 2. Known leptomeningeal involvement. 3. Advanced/metastatic, symptomatic, visceral spread, with a risk of life-threatening complications in the short-term (including patients with massive uncontrolled effusions \[pleural, pericardial, peritoneal\], pulmonary lymphangitis, and over 50% liver involvement). 4. Participation in another interventional clinical trial or treatment with any investigational drug within 4 weeks prior to study entry. 5. Any systemic anticancer therapy within 3 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, eg, mitomycin C and nitrosoureas, or anticancer immunotherapies, a washout period of 6 weeks was required. For patients in Cohort 2, this did not apply to the most recently received hormone therapy. 6. Major surgery or radiotherapy within 3 weeks of the first dose of study treatment. Patients who received prior radiotherapy to ≥25% of bone marrow were not eligible, irrespective of when it was received. 7. Persistent grade \>1 clinically-significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ Grade 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 was allowed. 8. History of hypersensitivity reaction or any toxicity attributed to trastuzumab, murine proteins, or any of the excipients that warranted permanent cessation of these agents (applicable for Cohort 1 only). 9. Previous exposure to vinorelbine (applicable for Cohort 1 triplet combination only). 10. Exposure to the following cumulative anthracycline doses: 1. Doxorubicin or liposomal doxorubicin \>360 mg/m². 2. Epirubicin \>720 mg/m². 3. Mitoxantrone \>120 mg/m² and idarubicin \>90 mg/m². 4. Other anthracycline at a dose equivalent to \>360 mg/m² doxorubicin 5. For patients having received \> 1 anthracycline, the cumulative dose must not exceed the equivalent of 360 mg/m² doxorubicin. 11. Chronic use of high-dose oral corticosteroid therapy (\>10 mg of prednisone equivalent per day). 12. Uncontrolled hypertension (systolic \>150 mmHg and/or diastolic \> 00 mmHg) or unstable angina. 13. History of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal supraventricular tachycardia). 14. History of myocardial infarction within 6 months of study entry. 15. History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma) within 3 years of study entry. 16. Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. 17. Current serious illness or medical conditions including, but not limited to uncontrolled active infection, clinically significant pulmonary, metabolic, or psychiatric disorders. 18. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. 19. Pregnant or lactating women; women of childbearing potential must use effective contraception methods (patient and/or partner, eg, surgical sterilization, a reliable barrier method) prior to study entry, for the duration of study participation, and for 7 months after the last dose of zenocutuzumab/trastuzumab. See Protocol Section 8.10. 20. Patients with only non-measurable lesions other than bone metastasis (eg, pleural effusion, ascites, or other visceral locations). 21. Patients with bone-only disease with blastic-only metastasis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate at 24 Weeks | 24 weeks | Clinical benefit rate (CBR) at 24 weeks per investigator assessment. CBR is the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR), or Stable Disease (SD) lasting 24 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Central Review | Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment) | For assessment per RECIST v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause. |
| Overall Response Rate (ORR) Per Investigator Assessment | Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment) | The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response). |
| Overall Response Rate (ORR) Per Central Review | Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment) | The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response). |
| Duration of Response (DoR) Per Investigator Assessment | Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment) | DoR applies only to patients with a Best Overall Response (BOR) of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DoR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause. |
| Progression Free Survival (PFS) Per Investigator Assessment | Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment) | For assessment per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause. |
| Overall Survival (OS) | Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment) | The time from treatment start until death due to any cause. |
| Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug | During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2). | Evaluation of number of participants with Adverse Events leading to leading to discontinuation of study drug |
| Number of Patients With AE's of Special Interest (AESI) | During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2). | AESIs for MCLA-128 combinations include: Infusion-related reactions (for any antibodies, known AESI for MCLA-128) Cardiotoxicity (anti-Human Epidermal Growth Factor Receptor (HER)2 therapy) Diarrhea (anti-HER2 therapy) Myelosuppression (vinorelbine) |
| Anti-drug Antibodies Serum Titers | Pre-dose for each of cycles 1, 3 and 5, and every 4 cycles thereafter, and at the End of Treatment visit. | Number of patients with anti-drug antibodies at baseline and on treatment |
| Duration of Response (DoR) Per Central Review | Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment) | DoR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DOR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause. |
Countries
Belgium, France, Netherlands, Portugal, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
For this study 105 were enrolled, but only 104 patients were treated. The non-treated patient was excluded prior to initiation of study treatment due to failure to meet inclusion criteria 2.2d (No progression under Cyclin-Dependent Kinase (CDK) inhibitor). \*Abbreviations used\* in this section: Progressive Disease (PD) Patient (PT) Tumor Assessment (TA)
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Doublet zenocutuzumab + trastuzumab
Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3
Trastuzumab: humanised IgG1 monoclonal antibody | 15 |
| Cohort 1 Triplet zenocutuzumab + trastuzumab + vinorelbine
Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3
Trastuzumab: humanised IgG1 monoclonal antibody
Vinorelbine: antineoplastic drug of vinca alkaloid family | 39 |
| Cohort 2 zenocutuzumab + endocrine therapy
Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3
Endocrine therapy: same endocrine therapy is administered as the last line of endocrine therapy | 50 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Lack of compliance | 0 | 1 | 0 |
| Overall Study | Progressive Disease (PD) | 15 | 30 | 47 |
| Overall Study | Scans showed PD 01JUL2019 (but the PT has received radiation and since TA05 the assessments are NE) | 0 | 1 | 0 |
| Overall Study | Subject withdrawal of all treatment and follow-up with agreement for contact | 0 | 2 | 0 |
| Overall Study | Subject withdrawal of all treatment and follow-up with disagreement for contact | 0 | 1 | 0 |
| Overall Study | Subject withdrawal of investigational product | 0 | 1 | 0 |
| Overall Study | symptomatic deterioration | 0 | 1 | 1 |
| Overall Study | Treating physician decision due to lack of clinical benefit for patient | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 Triplet | Cohort 1 Doublet | Total | Cohort 2 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 4 Participants | 27 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 11 Participants | 77 Participants | 39 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 12 | 53 years STANDARD_DEVIATION 12.1 | 56 years STANDARD_DEVIATION 12.1 | 57 years STANDARD_DEVIATION 12.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 12 Participants | 87 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 10 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 5 Participants | 23 Participants | 4 Participants |
| Race (NIH/OMB) White | 22 Participants | 9 Participants | 77 Participants | 46 Participants |
| Region of Enrollment Belgium | 0 participants | 2 participants | 10 participants | 8 participants |
| Region of Enrollment France | 18 participants | 9 participants | 47 participants | 20 participants |
| Region of Enrollment Netherlands | 2 participants | 1 participants | 4 participants | 1 participants |
| Region of Enrollment Portugal | 7 participants | 0 participants | 13 participants | 6 participants |
| Region of Enrollment Spain | 3 participants | 1 participants | 11 participants | 7 participants |
| Region of Enrollment United Kingdom | 1 participants | 0 participants | 3 participants | 2 participants |
| Region of Enrollment United States | 8 participants | 2 participants | 16 participants | 6 participants |
| Sex: Female, Male Female | 39 Participants | 15 Participants | 104 Participants | 50 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 1 / 39 | 1 / 50 |
| other Total, other adverse events | 15 / 15 | 39 / 39 | 48 / 50 |
| serious Total, serious adverse events | 2 / 15 | 8 / 39 | 9 / 50 |
Outcome results
Primary
Clinical Benefit Rate at 24 Weeks
Clinical benefit rate (CBR) at 24 weeks per investigator assessment. CBR is the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR), or Stable Disease (SD) lasting 24 weeks.
Time frame: 24 weeks
Population: Per-protocol efficacy set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 Doublet | Clinical Benefit Rate at 24 Weeks | 3 Participants |
| Cohort 1 Triplet | Clinical Benefit Rate at 24 Weeks | 18 Participants |
| Cohort 2 | Clinical Benefit Rate at 24 Weeks | 9 Participants |
Secondary
Anti-drug Antibodies Serum Titers
Number of patients with anti-drug antibodies at baseline and on treatment
Time frame: Pre-dose for each of cycles 1, 3 and 5, and every 4 cycles thereafter, and at the End of Treatment visit.
Population: Safety set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 Doublet | Anti-drug Antibodies Serum Titers | Treatment-boosted ADA | 0 Participants |
| Cohort 1 Doublet | Anti-drug Antibodies Serum Titers | Treatment-induced ADA | 0 Participants |
| Cohort 1 Doublet | Anti-drug Antibodies Serum Titers | On-treatment, ADA-Negative | 8 Participants |
| Cohort 1 Doublet | Anti-drug Antibodies Serum Titers | On-treatment, evaluable | 8 Participants |
| Cohort 1 Doublet | Anti-drug Antibodies Serum Titers | Baseline, Anti-Drug Antibody (ADA)-Negative | 12 Participants |
| Cohort 1 Doublet | Anti-drug Antibodies Serum Titers | On-treatment, ADA-Positive | 0 Participants |
| Cohort 1 Doublet | Anti-drug Antibodies Serum Titers | Baseline, ADA-Positive | 3 Participants |
| Cohort 1 Triplet | Anti-drug Antibodies Serum Titers | On-treatment, ADA-Positive | 0 Participants |
| Cohort 1 Triplet | Anti-drug Antibodies Serum Titers | Treatment-induced ADA | 0 Participants |
| Cohort 1 Triplet | Anti-drug Antibodies Serum Titers | Baseline, ADA-Positive | 9 Participants |
| Cohort 1 Triplet | Anti-drug Antibodies Serum Titers | Treatment-boosted ADA | 0 Participants |
| Cohort 1 Triplet | Anti-drug Antibodies Serum Titers | On-treatment, evaluable | 32 Participants |
| Cohort 1 Triplet | Anti-drug Antibodies Serum Titers | Baseline, Anti-Drug Antibody (ADA)-Negative | 29 Participants |
| Cohort 1 Triplet | Anti-drug Antibodies Serum Titers | On-treatment, ADA-Negative | 32 Participants |
| Cohort 2 | Anti-drug Antibodies Serum Titers | Treatment-boosted ADA | 0 Participants |
| Cohort 2 | Anti-drug Antibodies Serum Titers | Baseline, Anti-Drug Antibody (ADA)-Negative | 46 Participants |
| Cohort 2 | Anti-drug Antibodies Serum Titers | On-treatment, evaluable | 38 Participants |
| Cohort 2 | Anti-drug Antibodies Serum Titers | On-treatment, ADA-Negative | 35 Participants |
| Cohort 2 | Anti-drug Antibodies Serum Titers | On-treatment, ADA-Positive | 3 Participants |
| Cohort 2 | Anti-drug Antibodies Serum Titers | Treatment-induced ADA | 3 Participants |
| Cohort 2 | Anti-drug Antibodies Serum Titers | Baseline, ADA-Positive | 3 Participants |
Secondary
Duration of Response (DoR) Per Central Review
DoR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DOR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause.
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Population: Per-protocol efficacy set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Triplet | Duration of Response (DoR) Per Central Review | 6.36 months |
Secondary
Duration of Response (DoR) Per Investigator Assessment
DoR applies only to patients with a Best Overall Response (BOR) of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DoR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause.
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Population: Per-protocol efficacy set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Triplet | Duration of Response (DoR) Per Investigator Assessment | 4.21 months |
| Cohort 2 | Duration of Response (DoR) Per Investigator Assessment | 4.50 months |
Secondary
Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug
Evaluation of number of participants with Adverse Events leading to leading to discontinuation of study drug
Time frame: During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
Population: Safety set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 Doublet | Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug | 0 Participants |
| Cohort 1 Triplet | Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug | 1 Participants |
| Cohort 2 | Number of Patients With Adverse Events (AE's) Leading to Discontinuation of Study Drug | 3 Participants |
Secondary
Number of Patients With AE's of Special Interest (AESI)
AESIs for MCLA-128 combinations include: Infusion-related reactions (for any antibodies, known AESI for MCLA-128) Cardiotoxicity (anti-Human Epidermal Growth Factor Receptor (HER)2 therapy) Diarrhea (anti-HER2 therapy) Myelosuppression (vinorelbine)
Time frame: During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
Population: Safety set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 Doublet | Number of Patients With AE's of Special Interest (AESI) | Cardiotoxicity (anti-HER2 therapy) | 1 Participants |
| Cohort 1 Doublet | Number of Patients With AE's of Special Interest (AESI) | Diarrhea (anti-HER2 therapy) | 7 Participants |
| Cohort 1 Doublet | Number of Patients With AE's of Special Interest (AESI) | Infusion-related reaction | 1 Participants |
| Cohort 1 Doublet | Number of Patients With AE's of Special Interest (AESI) | Myelosuppression (vinorelbine) | NA Participants |
| Cohort 1 Triplet | Number of Patients With AE's of Special Interest (AESI) | Myelosuppression (vinorelbine) | 18 Participants |
| Cohort 1 Triplet | Number of Patients With AE's of Special Interest (AESI) | Cardiotoxicity (anti-HER2 therapy) | 3 Participants |
| Cohort 1 Triplet | Number of Patients With AE's of Special Interest (AESI) | Infusion-related reaction | 7 Participants |
| Cohort 1 Triplet | Number of Patients With AE's of Special Interest (AESI) | Diarrhea (anti-HER2 therapy) | 28 Participants |
| Cohort 2 | Number of Patients With AE's of Special Interest (AESI) | Myelosuppression (vinorelbine) | NA Participants |
| Cohort 2 | Number of Patients With AE's of Special Interest (AESI) | Diarrhea (anti-HER2 therapy) | 17 Participants |
| Cohort 2 | Number of Patients With AE's of Special Interest (AESI) | Infusion-related reaction | 12 Participants |
| Cohort 2 | Number of Patients With AE's of Special Interest (AESI) | Cardiotoxicity (anti-HER2 therapy) | 0 Participants |
Secondary
Overall Response Rate (ORR) Per Central Review
The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Population: Per-protocol efficacy set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 Doublet | Overall Response Rate (ORR) Per Central Review | 0 Participants |
| Cohort 1 Triplet | Overall Response Rate (ORR) Per Central Review | 6 Participants |
| Cohort 2 | Overall Response Rate (ORR) Per Central Review | 0 Participants |
Secondary
Overall Response Rate (ORR) Per Investigator Assessment
The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Population: Per-protocol efficacy set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 Doublet | Overall Response Rate (ORR) Per Investigator Assessment | 0 Participants |
| Cohort 1 Triplet | Overall Response Rate (ORR) Per Investigator Assessment | 10 Participants |
| Cohort 2 | Overall Response Rate (ORR) Per Investigator Assessment | 1 Participants |
Secondary
Overall Survival (OS)
The time from treatment start until death due to any cause.
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Population: Per-protocol efficacy set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Doublet | Overall Survival (OS) | 14.09 months |
| Cohort 1 Triplet | Overall Survival (OS) | 27.33 months |
| Cohort 2 | Overall Survival (OS) | 26.41 months |
Secondary
Progression Free Survival (PFS) Per Central Review
For assessment per RECIST v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause.
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Population: Per-protocol efficacy set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Doublet | Progression Free Survival (PFS) Per Central Review | 1.41 months |
| Cohort 1 Triplet | Progression Free Survival (PFS) Per Central Review | 5.59 months |
| Cohort 2 | Progression Free Survival (PFS) Per Central Review | 1.45 months |
Secondary
Progression Free Survival (PFS) Per Investigator Assessment
For assessment per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause.
Time frame: Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
Population: Per-protocol efficacy set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Doublet | Progression Free Survival (PFS) Per Investigator Assessment | 1.41 months |
| Cohort 1 Triplet | Progression Free Survival (PFS) Per Investigator Assessment | 5.52 months |
| Cohort 2 | Progression Free Survival (PFS) Per Investigator Assessment | 2.61 months |