Inclusion Criteria:
1. Willing and able to provide informed consent prior to start of any study procedures
and assessments and must be willing to comply with all study procedures.
2. Adult participants ≥ 18 years of age.
3. Participants with a documented history of histopathologically confirmed metastatic
NSCLC, SCLC, TNBC, cutaneous melanoma, HNSCC, and endometrial cancer with documented
disease progression during or after their most recent line of anticancer therapy.
Participants must be refractory to or have refused standard of care therapy
(including PD-1/PD-L1 inhibitors), or have no standard of care therapy available
that is likely to provide clinical benefit.
4. Participants with PD-L1 positive NSCLC, SCLC, TNBC, cutaneous melanoma, HNSCC, and
endometrial cancer:
- - If the participant tumour's PD-L1 expression status is unknown, PD-L1
positivity may be determined in a pre-screening step whereby the participant
may be approached to provide written informed consent to have their tumour
tissue undergo IHC testing as determined by a validated test (tumour tissue may
be obtained from archived samples or from a freshly obtained biopsy).
- - Any number of prior treatment lines are allowed.
5. Must have at least 1 measurable target lesion according to RECIST version 1.1.
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
7. Participants must have a life expectancy of ≥ 4 months in the opinion of the
Investigator.
8. Women of childbearing potential (WOCBP) must have a negative beta-human chorionic
gonadotropin (β-hCG) test and must not be breastfeeding. WOCBP are defined as those
who are not surgically sterile or post-menopausal. Female participants will be
considered post-menopausal if they have been amenorrheic for 12 months without an
alternative medical cause. Female participants < 50 years old who meet the criteria
for post-menopausal status without previous surgical sterilisation should be
considered for further investigation with luteinising hormone (LH) and follicle
stimulating hormone (FSH) levels to confirm serological post-menopausal status.
9. WOCBP must agree to use a highly effective method of contraception during the study
and for 14 days after the last injection of 177Lu-RAD204im and/or 6 months after the
last dose of 177Lu-RAD204tr, whichever occurs later. Acceptable methods of
contraception are described in Section 13.3 of the Protocol.
10. Male participants who are able to father a child must agree to avoid impregnating a
partner and to adhere to a highly effective method of contraception during the study
and for 14 days after the last injection of 177Lu-RAD204im and/or 6 months after the
last dose of 177Lu-RAD204tr, whichever occurs later. All male participants must
agree to not donate sperm during the study and for 14 days after the last injection
of 177Lu-RAD204im and/or 6 months after the last dose of Lu-RAD204tr, whichever
occurs later. Acceptable methods of contraception are described in Section 13.3 of
the Protocol.
11. Participants with previously treated brain metastases are eligible to participate
if:
- - they are neurologically and radiologically stable (no evidence of progression
by imaging; same imaging modality [magnetic resonance imaging (MRI) or computed
tomography (CT) scan] must be used for each assessment) for at least 28 days
prior to the first dose of 177Lu-RAD204,
- do not require steroids to treat associated neurological symptoms, and.
- - have no history of leptomeningeal disease or spinal cord compression.
12. For Phase I:
- - Participants must have positive lesion(s) by 177Lu-RAD204im SPECT/CT per
central review as described in Image Review Charter, and.
- - Participants without any positive lesion by 177Lu-RAD204im SPECT/CT, e.g. due
to poor image quality, may be allowed to enrol on a case-by-case basis at the
discretion of the Principal Investigator and in discussion with study Sponsor,
provided the participant's tumour is known to express PD-L1.
Exclusion Criteria:
1. History of prior organ transplant.
2. Any other known, active malignancy, except for treated cervical intraepithelial
neoplasia or non-melanoma skin cancer. Patients with a history of malignancies of
low recurrence potential who have received curative-intent therapy may be approved
on a case-by-case basis in discussion with study Sponsor, if it is determined not to
put the patient at an increased risk of adverse drug effects and/or interfere with
the integrity of study outcome.
3. Have any medical condition that would, in the Investigator's judgment, prevent the
participant's full participation in the clinical study due to safety concerns or
compliance with clinical study procedures such as participants with severe
claustrophobia who are unresponsive to oral anxiolytics, participants with low back
pain who cannot lie comfortably on an imaging table, participants who are
hyperactive or hyperkinetic such that they cannot tolerate lying still for multiple
time point imaging procedures, etc.
4. Residual toxicity ≥ Grade 2 from prior anti-cancer therapy (except alopecia).
5. History of uncontrolled allergic reactions and/or known or expected hypersensitivity
to protein therapeutics, 177Lu-RAD204 or any of its excipients.
6. Inadequate organ functions as reflected in laboratory parameters:
- - Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) <
60 mL/min.
- - Platelet count of < 100 × 109/L.
- - Absolute neutrophil count (ANC) < 1.5 × 109/L.
- - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN,
or > 5 × ULN for patients with known liver metastases.
- - Total bilirubin > 1.5 × ULN, except for patients with documented Gilbert's
syndrome who are eligible if total bilirubin ≤ 3 × ULN.
- - For participants not taking warfarin or other anticoagulants: international
normalised ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; and either
partial thromboplastin time or activated partial thromboplastin time (PTT or
aPTT) ≤ 1.5 × ULN.
Participants taking warfarin must be on a stable dose that
results in a stable INR < 3.5. Among participants receiving other anticoagulant
therapy, PT or aPTT must be within the intended therapeutic range of the
anticoagulant.
7. Patients requiring blood product transfusion within 4 weeks of first dose of
177Lu-RAD204tr are not eligible to participate.
8. Clinically significant cardiovascular disease including but not limited to:
- - Acute myocardial infarction within 6 months prior to screening.
- - New York Heart Association (NYHA) Class II or greater congestive heart failure
(see Section 20.6)
- Clinically significant abnormalities in rhythm, conduction or morphology on
resting ECG (e.g. complete left bundle branch block, third degree heart block)
- Uncontrolled hypertension.
- - Known LVEF < 50%
- QTcF > 470 msec for females and QTcF > 450 msec for males on screening
electrocardiogram (ECG) or congenital long QT syndrome.
9. Participation in any other investigational trial at the time of informed consent
signature.
10. Pregnant or lactating women.
The following exclusion criteria applies to participants in Phase I:
11. Major surgery within 4 weeks prior to first dose of 177Lu-RAD204tr.
12. Received anti-cancer therapy, including chemotherapy, immunotherapy, radiation
therapy, biologic, herbal therapy, or any investigational therapy or investigational
device, within 28 days (or 5 half-lives for biologic/non-cytotoxic agents, whichever
is shorter), prior to the first dose of 177Lu-RAD204tr.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent, or
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.
CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or
higher immune-mediated AE.
NOTE: endocrine immune-mediated AEs that are controlled with replacement therapy are
allowed.
14. Has had or is scheduled to have major surgery < 28 days prior to the first dose of
177Lu-RAD204tr.
15. Positive status for human immunodeficiency virus (HIV).
16. Active or chronic hepatitis B or C. Chronic hepatitis B or hepatitis C with
undetectable viral loads on stable suppression therapy may be allowed on a
case-by-case basis in discussion with study Sponsor.
17. Any medical condition which, in the opinion of the Investigator, places the
participant at an unacceptably high risk for toxicities.
18. Any uncontrolled intercurrent illness or clinically significant uncontrolled
condition(s), including but not limited to active bacterial, fungal, or viral
infections requiring systemic therapy.
