| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid tumors expressing folate receptor alpha in 4 tumor types: platinum resistant ovarian cancer, triple-negative breast cancer (TNBC), endometrial cancer (EC), and non-small cell lung cancer adenocarcinoma; NSCLC). |
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| E.1.1.1 | Medical condition in easily understood language |
| To investigate ovarian cancer, breast cancer, endometrial cancer and lung cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014733 |
| E.1.2 | Term | Endometrial cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objectives
Dose-Escalation Part primary objective:
(1) To evaluate safety, tolerability and to determine the recommended Phase 2 dose (RP2D) of MORAb-202 in subjects with selected tumor types (ovarian cancer [OC], endometrial cancer [EC], non-small cell lung carcinoma [NSCLC], triple-negative breast cancer [TNBC]).
Dose-Confirmation Part primary objectives:
To further evaluate the safety and tolerability of MORAb-202.
To evaluate preliminary efficacy measured by objective response rate (ORR) of MORAb-202 in subjects with OC and EC at selected doses.
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
- To evaluate duration of response (DOR), disease control rate (DCR), and clinical benefit rate (CBR).
- To evaluate progression-free survival (PFS) and overall survival (OS).
- To determine the pharmacokinetic (PK) profiles of MORAb-202, total antibody, and released eribulin in serum or plasma.
-To evaluate the relationship between folate receptor alpha (FRA) expression levels and clinical outcome measures to support the identification of an appropriate FRA cut off point.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged ≥18 years
2. For Dose-Escalation: Females (TNBC, EC and OC) or males/females (NSCLC adenocarcinoma). Subjects with the following disease characteristics:
a. TNBC:
Histologically confirmed diagnosis of metastatic TNBC (ie, estrogen receptor (ER) negative/progesterone receptor negative/ human epidermal growth factor receptor 2 (HER2) negative (defined as IHC <2+ or fluorescence in situ hybridization (FISH) negative) breast cancer). Previously treated with at least one line of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting.
b. NSCLC adenocarcinoma:
Histologically or cytologically confirmed metastatic NSCLC adenocarcinoma: subjects who have failed previous treatment for metastatic disease, are not indicated or failed epidermal growth factor receptor (EGFR)-, ALK-, BRAF- or ROS1-targeted therapy, and for whom no alternative standard therapy exists
c. EC:
Histologically confirmed diagnosis of advanced, recurrent or metastatic EC. Relapsed or failure of at least one platinum-based regimen or one immunotherapy-based regimen.
d. Ovarian cancer or primary peritoneal cancer or fallopian tube cancer:
Histologically confirmed diagnosis of high grade serous epithelial OC or primary peritoneal cancer or fallopian tube cancer.
Subjects must have:
platinum-resistant disease (defined as progression within 6 months after the last dose of at least 4 cycles of the last platinum containing chemotherapy regimen) received up to 4 lines of systemic therapy post development of platinum resistance.
For Dose-Confirmation:
-Ovarian cancer or primary peritoneal cancer or fallopian tube cancer.
-EC: Histologically confirmed diagnosis of advanced, recurrent, or metastatic EC.
3. Available tumor tissue for FRA expression (%) by IHC analysis as assessed by the vendor
4. Radiological disease progression on or after the most recent therapy by investigator assessment.
5. Measurable disease meeting the following criteria (confirmed by central radiographic review, in the Dose-Confirmation Part only):
- At least one lesion of >1.0 cm in long axis diameter for non-lymph nodes or >1.5 cm in short axis diameter for lymph nodes that is serially measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 using either CT or MRI,
- Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show evidence of PD based on RECIST 1.1 to be deemed a target lesion.
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
7. Subjects who are expected to survive a minimum of 3 months after the first administration of the study drug.
8. Adequate renal function as defined in the protocol .
9. Adequate bone marrow function as defined in the protocol.
Growth factors or transfusions, as per institutional practice, are allowed if needed to achieve the above values. Growth factor and platelet transfusion should not be used within 7 days of initiation of study treatment.
10. Adequate liver function as defined in the protocol
11. Subjects must undergo a washout period required from the end of prior treatment to the first administration of the study drug.
12. Patients with a history of deep vein thrombosis (DVT) within 3 months prior must have completed at least 1 month of anticoagulation prior to starting study treatment
13.Patients at risk for DVT secondary to central venous catheters or with past medical history of DVT or clinical symptoms suggestive of DVT must have venous Doppler ultrasonography to rule out DVT during the screening period and prior to initiation of study treatment
14. If a subject has undergone major surgery, the subject must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
15. Resolution of anticancer therapy-related or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (Grade ≤2), anemia (Hgb ≥9.0 g/dL), and alopecia (any grade).
16. Subject must be willing and able to comply with all aspects of the protocol.
17.Subject must provide written informed consent prior to any study-specific screening procedures. |
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| E.4 | Principal exclusion criteria |
1-Subjects with endometrial leiomyosarcoma, endometrial stromal sarcoma or high-grade sarcoma.
2-Subjects who received previous treatment with any folate receptor targeting agents.
3-Subjects with platinum refractory OC
4- Currently enrolled in another clinical study or used any investigational drug or device.
5-Subjects with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 2 weeks before starting treatment in this study.
6-Diagnosed with meningeal carcinomatosis.
7-Any other invasive malignancy that required treatment (other than definitive surgery) or has shown evidence of recurrence/progression (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ) during the 2 years prior to starting study treatment.
8-Significant cardiovascular impairment.
9-Clinically significant ECG abnormality.
10-Known to be Human Immunodeficiency Virus (HIV) positive.
11-Active viral hepatitis (B or C as demonstrated by positive serology).
12-Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first administration of the study drug.
13-Females of childbearing potential who:
•within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following:
•total abstinence (if it is their preferred and usual lifestyle)*
•an intrauterine device or intrauterine hormone-releasing system (IUS)
•a contraceptive implant
•an oral contraceptive (subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 90 days after study drug discontinuation)
•have a vasectomized partner with confirmed azoospermia
•do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 90 days after study drug discontinuation.
14- For Dose-Escalation only: Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period and for 90 days after study drug discontinuation). If the female partner is pregnant, then males who do not agree to use latex or synthetic condoms throughout the study period and for 90 days after study drug discontinuation. No sperm donation is allowed during the study period and for 90 days after study drug discontinuation.
15-Pulmonary Function Test (PFT) abnormalities: FEV1/FVC <0.7, FEV1 or FVC <80%, DLCO <80%.
16-Current ILD/pneumonitis, or ILD/pneumonitis is suspected at Screening or history interstitial lung disease (ILD)/pneumonitis of any severity including ILD/pneumonitis from prior anticancer therapy.
17-Current infectious pneumonia, history of viral pneumonia (including COVID-19–related infection) with evidence of persistent radiologic abnormalities.
18-Lung-specific clinically significant illnesses and restrictive lung disease.
19-Clinically significant pleural or pericardial effusion requiring drainage or ascites requiring peritoneal shunt.
20-Prior pneumonectomy.
21- History of chest radiotherapy. Subjects with history of chest wall radiation (eg, history of breast cancer) may be permitted if chest wall radiation is documented > 2 years before starting study treatment.
22-Any autoimmune, connective tissue, or inflammatory disorders where there is documented (or suspicion of) pulmonary involvement.
23-A known history of active TB (bacillus tuberculosis).
24-Scheduled for surgery during the study, other than minor surgery which would not delay study treatment.
25-An active clinically significant (in the opinion of the Investigator) infection requiring systemic therapy within 2 weeks prior to the first dose of study drug.
26-Administration of a live, attenuated vaccine within 4 weeks prior to the first dose of study drug, or anticipation that such a live attenuated vaccine will be required during the study.
27-Any prior hypersensitivity to monoclonal antibodies and/or contraindication to the receipt of corticosteroids or any of the excipients
28-Known intolerance to either of the components of the study drug.
29-Any medical or other condition which, in the opinion of the investigator would preclude the subject’s participation in the clinical study.
30-Receiving any medication prohibited in combination with the study treatment(s), as described in the product label for eribulin, unless medication was stopped within 7 days prior to enrollment.
31-Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints are:
RP2D of MORAb-202 (Dose-Escalation Part only).
ORR: defined as the proportion of subjects achieving a best overall response (BOR) of complete response (CR) or partial response (PR) (BOR - are CR, PR, SD, PD, and not evaluable (NE), where SD has to be achieved at ≥5 weeks after the first dose 24 weeks after C1D1. All responses of CR and PR must be confirmed no less than 28 days following the initial achievement of the response.
Safety Endpoints: DLTs, AEs,(SAEs, AEs leading to treatment discontinuation) and AEIs (including ILD incidence, severity, duration and outcome, and deaths). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Efficacy analyses will be conducted based on the Efficacy Analysis Set. The primary efficacy analysis for a tumor type will be performed when all subjects in the cohort have completed the Week 24 tumor assessment or discontinued study treatment or when the study is terminated by the sponsor. |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints of the study are DOR, DCR, CBR, PFS by RECIST 1.1, and OS.
Other secondary endpoints of the study include safety endpoints, PK profile, and the relationship between FRA expression levels and clinical outcome:
Safety Endpoints: clinical laboratory tests, vital signs, oxygen saturation, body weight, 12-lead ECGs, ECOG PS, and serum ADA titer (semi-quantitative test) (not identified in an ongoing manner, identified during study analyses).
The PK profile of MORAb-202/total antibody/released eribulin in serum and plasma, and the assessment of potential ADA to MORAb-202.
The relationship between FRA expression levels and clinical outcome. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DOR:From the 1st date of documented CR or PR to the date of disease progression or death, whichever occurs first. Calculated for subjects whose BOR is CR or PR.
DCR:Proportion of subjects with BOR of CR, PR, or SD.
CBR:Proportion of subjects with BOR of CR, PR, or durable SD (≥23 weeks). SD is defined as the time from the date of 1st dose to the date of the 1st documentation of disease progression or death, whichever occurs first. Calculated for subjects whose BOR is SD.
PFS:From the date of 1st dose to the date of the 1st documentation of disease progression or death, whichever occurs first.
OS:From the date 1st dose to the date of death or for the subjects alive or lost to follow up, date of last known alive or the date of data cutoff, whichever comes first.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
last subject/last visit or the time that the sponsor terminates the study
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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