Inclusion
Inclusion Criteria for Part 1 (Molecular Pre-Screening):
1. Participant has provided consent.
2. 18 years to 80 years of age on the day of consent.
3. Life expectancy greater than or equal to 6 months according to Investigator’s best judgement.
4. ECOG performance status 0 or 1.
5. Diagnosis of confirmed NSCLC with an activating EGFRm known to confer sensitivity to EGFR TKIs.
6. Receiving stable maintenance dose of osimertinib (80 mg daily) for at least 6 months prior to enrolment.
7. No evidence of radiological progression of disease (by computed tomography [CT] scan performed within 6 weeks prior to study enrolment) based on RECIST v1.1
8. Peripheral venous access or access via central venous catheter or implantable port system is sufficient and suitable for repeated venipuncture
Inclusion Criteria for Part 2 (Dose Escalation):
1. Participant (or legally authorised representative) has voluntarily agreed to study participation by giving written informed consent.
2. Participant must be 18 years to 80 years.
3. Life expectancy greater than or equal to 3 months.
4. ECOG performance status 0 or 1.
5. Diagnosis of confirmed NSCLC with an activating EGFR mutation known to confer sensitivity to EGFR TKIs.
6. Receiving stable maintenance dose of osimertinib (80 mg daily) for at least 6 months prior to enrolment.
7. Any of the following during the Part 1 molecular pre-screening phase:
a. Radiological (by CT) progressive, measurable or evaluable disease by RECIST v1.1; or
b. a positive activating EGFRm ctDNA result.
8. Adequate haematological, liver, and kidney function as follows:
a. Bone marrow reserve:
i. Absolute neutrophil count greater than or equal to 1.5 × 10^9/L without growth factor support in the 2 weeks prior to study entry.
ii. Haemoglobin greater than or equal to 90 g/L without transfusion and/or without growth factor support in 2 weeks prior to study entry.
iii. Platelet count greater than or equal to 100 × 10^9/L without transfusion in 2 weeks prior to study entry.
b. Hepatic function:
i. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 3 × upper limit of normal (ULN; less than or equal to 5 × ULN if liver metastases)
ii. Total bilirubin less than or equal to 1.5 x ULN if no liver metastases, or < 3 x ULN in presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.
c. Renal Function:
i. Serum creatinine less than or equal to 1.5 x ULN or serum creatinine clearance (CrCL) greater than 50 mL/min, as per the Cockcroft-Gault Equation.
9. Adequate cardiac function at screening, as determined by:
a. Systolic blood pressure less than 160 mm Hg and diastolic blood pressure less than 100 mm Hg (Grade less than or equal to 2) including with the use of antihypertensive therapy
b. Left ventricular ejection fraction (LVEF) greater than or equal to 50% by echocardiogram
c. No clinically significant ECG waveform abnormalities.
d. QTcF less than or equal to 470 msec, as determined by the mean QTcF values from the ECG assessments at screening (one triplicate)
10. International normalised ratio (INR) /prothrombin time < 2 x ULN, activated partial thromboplastin time (aPTT) less than or equal to 1.5 xULN.
11. Female participants must not be pregnant or lactating, and must be
a. Surgically sterile, or
b. Use highly effective contraceptive method or intrauterine hormone-releasing system used for at least 4 weeks prior to screening, and condom for male partner from screening until at least 30 days after the last administration of study drug, or
c. Post-menopausal for greater than or equal to 12 months, or
d. Female participants who are abstinent from heterosexual intercourse as part of their usual lifestyle will also be eligible for participation.
12. Women of childbearing potential (WOCBP) must agree to abstain from egg donation through 30 days after the last administration of study drug.
13. Males must be:
a. Surgically sterile (> 90 days since vasectomy with documentation of azoospermia 90 days after procedure) and agree to use a condom from screening at least 90 days after the last administration of study drug, or
b. Abstinent from heterosexual intercourse as part of their usual lifestyle, or
c. If engaged in sexual relations with a WOCBP, the female partner of male participant must either be surgically sterile or,
d. Use an acceptable, highly effective contraceptive method from screening at least 90 days after the last administration of study drug. Acceptable methods of contraception include simultaneous use of condoms and effective contraceptive for the female partner (WOCBP) that includes: OCPs, long-acting implantable hormones, injectable hormones, a vaginal ring or an IUD used for at least 4 weeks prior to screening.
14. Male participants must agree to refrain from donating sperm from screening until at least 90 days after the last administration of study drug.
15. Peripheral venous access or access via central venous catheter or implantable port system is sufficient and suitable for repeated venipuncture
Exclusion
Exclusion Criteria for Part 1 - Molecular Pre-Screening:
1. Participation in a concurrent interventional trial.
2. Persisting Grade 2 or higher severity AEs (except alopecia and neuropathy) from prior antitumour treatment, including as a result of maintenance osimertinib therapy, as per NCI-CTCAE v5.0.
Exclusion Criteria for Part 2 (Dose Escalation):
1. Females who are pregnant or lactating.
2. Participants with bronchial (including atelectasis), mediastinal, pleural or vascular involvement.
3. Have received cancer-directed therapy within the following timeframes:
a. Antitumour therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy or investigational agent) within 28 days prior to the first dose of RC220 (or 5 times the half-life if shorter than 28 days), except for osimertinib.
Note: exceptions may be considered on a case-by-case basis, as approved by the Sponsor Medical Monitor (MM) based on pharmacology.
b. Wide-field radiation therapy within 28 days (or palliative radiation therapy within 7 days) prior to the first dose of RC220, or the participant has not recovered from the side effects of radiation therapy in the opinion of the Investigator.
Note: Limited radiation to oligometastatic lesions (up to 3 at a time) is permitted.
c. Any other concurrent investigational device(s), investigational agent(s) or conventional agent(s) within 28 days (unless 5 times the half-life is shorter than 28 days) prior to the first dose of RC220.
d. Therapeutic radiopharmaceuticals must be stopped 8 weeks prior to the first dose of RC220.
4. Persisting Grade 2 or higher severity AEs (except alopecia and neuropathy) from prior antitumour treatment, including as a result of maintenance osimertinib therapy, as per NCI-CTCAE v5.0.
5. Participants with primary CNS malignancy, symptomatic CNS metastases, meningeal metastases, carcinomatous meningitis or leptomeningeal disease.
Note: Participants with asymptomatic CNS metastases are eligible if clinically controlled.
6. Had major surgery within 28 days of the screening visit. Exception: no waiting period applies following central venous catheter placement.
7. History of tissue or organ transplantation.
8. Treatment with systemic immunosuppressive or myelosuppressive medications within 4 weeks prior to the first dose of RC220 that would, in the opinion of the Investigator, increase the risk of serious neutropenic complications. Exceptions: daily prednisone or
equivalent less than or equal to 10 mg/day; topical, inhaled or intranasal corticosteroids.
9. History of severe infection deemed clinically significant by the Investigator or designee within 4 weeks, or signs and symptoms of any active infection within 2 weeks prior to the first dose of RC220.
10. Active hepatitis B or C. Note: Hepatitis B virus (HBV) carriers without active disease (HBV DNA titre < 1000 copies/mL or 200 IU/mL) or cured hepatitis C (negative HCV RNA test) with confirmed viral clearance that are not receiving ongoing treatment and without residual chronic liver disease may be enrolled.
11. Confirmed human immunodeficiency virus (HIV) infection and receiving anti-retroviral therapy (ART). Participants with well controlled HIV infection (i.e., CD4+ count >350 cells per microlitre and viral copies less than 400/mL after at least 4 weeks of ART) may be eligible per discretion of the Investigator and with approval from Sponsor MM.
12. Participants with any inherited predisposition to bleeding or to thrombosis (von Willebrand disease, haemophilia, etc.). Participants with a history of nontraumatic haemorrhage (i.e., end stage liver disease, any haemorrhage requiring medical intervention), thromboembolic event or any condition which may increase bleeding risk including clotting disorders, thrombocytopenia during the last 3 months prior to the first dose of RC220.
13. Any other disease or clinically significant abnormality in laboratory parameters, including serious medical or psychiatric illness/condition, which in the judgement of the Investigator might compromise the safety of the participant or integrity of the study, interfere with participation in the trial or compromise the trial objectives.
14. Known allergies, hypersensitivity, or intolerance to the study drugs (RC220, osimertinib), or excipients.
15. Any known, documented, or suspected history of illicit substance abuse that would preclude study participation. Exception: Physician-prescribed medicinal opioids or cannabinoids are allowed for pain management, at the discretion of the Investigator and
in consultation with the Sponsor MM, as required.
16. Vaccination with any live vaccine within 4 weeks prior to the first dose of study treatment.
17. Use of new prescription or non-prescription medications, including complementary medicines, if the medication is a potential inhibitor of cytochrome P450 (CYP) isoform 3A4 and/or P-glycoprotein (P-gp), or if the medication is an inducer of CYP3A4 or P-gp,
throughout study participation.
18. Severe or uncontrolled cardiac disease requiring treatment, CHF (New York Heart Association) NYHA III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the 6 months prior to screening, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).
19. History of pneumonitis or interstitial lung disease.
20. Judgement by the Investigator that the participant is unlikely to comply with study procedures, restrictions and requirements.
21. Psychological, familial, sociological, or geographical conditions that are likely to interfere with compliance to the protocol.