Morab 202

1. Aged ≥ 18 years.

2. Females (TNBC, endometrial and ovarian cancer) or males/females (NSCLC adenocarcinoma). Subjects with the following disease characteristics:

TNBC: Histologically confirmed diagnosis of metastatic TNBC Previously treated with at least one line of systemic anticancer therapy (cytotoxic or targeted anticancer agents) in the metastatic setting.

NSCLC adenocarcinoma: Histologically or cytologically confirmed metastatic NSCLC adenocarcinoma: subjects who have failed previous treatment for metastatic disease, are not indicated or failed EGFR- ALK-, BRAF- or ROS1-targeted therapy, and for whom no alternative standard therapy exists.

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.

Ovarian cancer or primary peritoneal cancer or fallopian tube cancer: Histologically confirmed diagnosis of high grade serous epithelial ovarian cancer 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.

3. FRA-positive tumours (in the Expansion Part only). FRA expression to be assessed by IHC at a central laboratory using formalin-fixed, paraffin-embedded tissue samples. FRA positivity is defined as membrane staining in ≥ 5% of neoplastic cells at any intensity level.

4. Available tumour tissue for FRA expression analysis. Either archival tissue or newly obtained biopsies are acceptable if obtained under standard of care.

5. Radiological disease progression on or after the most recent therapy by investigator assessment.

6. Measureable disease meeting the following criteria (confirmed by central radiographic review, in the Expansion 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 RECIST 1.1 using either CT or MRI,

- Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show evidence of PD based on RECIST 1.1 to be deemed a target lesion.

7. Eastern Cooperative Oncology Group Performance Status of 0 or 1.

8. Subjects who are expected to survive a minimum of 3 months after the first administration of the study drug.

9. Adequate renal function as evidenced by serum creatinine ≤ 1.5 mg/dL or calculated creatinine clearance ≥ 50 mL/minute according to a 12 or 24 hour urine collection.

10. Adequate bone marrow function, as evidenced by:

- ANC ≥ 1.0 × 109/L

- Haemoglobin (Hgb) ≥ 9.0 g/dL

- Platelet count ≥ 75 × 109/L.

11. Adequate liver function, as evidenced by:

- Total bilirubin ≤ 1.5 × upper limit of normal except for unconjugated hyperbilirubinemia (e.g. Gilbert’s syndrome)

- Alkaline phosphatase, Alanine aminotransferase and aspartate aminotransferase ≤ 3 × ULN (in the case of liver metastases ≤ 5 × ULN). In case ALP is > 3 × ULN (in absence of liver metastases) or > 5 × ULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific ALP isoenzyme must be separated from the total and used to assess the liver function instead of the total ALP.

- Albumin > 3.0 g/dL.

12. Subjects must undergo a washout period required from the end of prior treatment to the first administration of the study drug that will be as follows:

Prior anticancer therapy:

- Prior chemotherapy, surgical therapy, radiation therapy: > 3 weeks.

- Antibody and other biologic therapeutic agents: ≥ 4 weeks.

- Endocrine therapy or, small-molecule targeted therapy: > 2 weeks.

- Immunotherapy ≥ 4 weeks. Supportive therapies:

- Blood/platelet transfusion, hematopoietic stimulating agent including granulocyte colony-stimulating factor formulation: ≥ 2 weeks.

13. 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.

14. Resolution of anticancer therapy-related or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (Grade ≤ 2), anaemia (Hgb ≥ 9.0 g/dL), and alopecia (any grade).

15. Subject must be willing and able to comply with all aspects of the protocol.

16. Subject must provide written informed consent prior to any study-specific screening procedures. 

1. Subjects who received previous treatment with any folate receptor targeting agents.

2. Subjects with platinum refractory ovarian cancer.

3. Currently enrolled in another clinical study within the past 28 days of any investigational drug preceding informed consent.

4. 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 4 weeks before starting treatment in this study.Any signs or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.

5. Diagnosed with meningeal carcinomatosis.

6. Any other malignancy that required treatment 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.

7. Significant cardiovascular impairment. History within 6 months prior to the first dose of study drug of: congestive heart failure; angina; myocardial infarction; stroke; cardiac arrhythmia associated with hemodynamic instability.

8. Clinically significant ECG abnormality.

9. Previously known to be HIV positive.

10. Active viral hepatitis (B or C).

11. Females who are breastfeeding or pregnant at Screening or Baseline.

12. 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 vasectomised 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.

For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, i.e. double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide.

NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrhoeic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically at least 1 month before dosing.

13. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (i.e. 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.

14. Any history of non-infectious pneumonitis or current pneumonitis.

15. Currently has active, or a history of, ILD.

16. Has a known history of active TB.

17. Scheduled for surgery during the study, other than minor surgery which would not delay study treatment.

18. Has an active infection requiring systemic therapy within 4 weeks prior to the first dose of study drug.

19. 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. Inactivated vaccines (such as hepatitis A or polio vaccines) are permitted during the study. Seasonal influenza vaccines that do not contain live virus are permitted.

20. Known intolerance to either of the components of the study drug.

21. Any medical or other condition which, in the opinion of the investigator would preclude the subjects participation in the clinical study.

22. Is 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 enrolment.

23. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 

Research Nurse: Lizzie Coates (x2031) Elizabeth.Coates@LTHTR.nhs.uk