Phase 1 Trial of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Activity of RP-1664 in Participants With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: Repare Therapeutics

 
 
 
 
 
 
 
 
Protocol Full Title: 
Phase 1 Trial of the Safety, Pharmacokinetics, Pharmacodynamics, and 
Preliminary Clinical Activity of RP-1664 in Participants with Advanced Solid 
Tumors 
Sponsor 
Confidentiality 
Statement: 
This document is confidential. It contains proprietary information of Repare 
Therapeutics (the sponsor). Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or performing 
this trial. 
GCP Statement 
This trial is to be performed in full compliance with International Council for 
Harmonization (ICH) of Technical Requirements for Pharmaceuticals for 
Human Use and all applicable local Good Clinical Practice (GCP) guidelines 
and regulations. All required trial documentation will be archived as required 
by regulatory authorities. 
Protocol Number: 
RP-1664-01 
Version: 
3.0 
Amendment 
Number: 
2 
Compound 
Number(s): 
RP-1664 
Trial Phase: 
Phase 1 
Acronym: 
LIONS (PLK4 Inhibitor in Advanced Solid Tumors) 
Short Title: 
Phase 1 First-in-Human Trial of RP-1664 in Participants with Advanced 
Solid Tumors 
Sponsor Name and 
Address: 
Repare Therapeutics  
7171 Frederick-Banting 
Building 2 
St-Laurent, Quebec, H4S 1Z9  
Canada 
Regulatory Agency 
Identifier Number(s): 
IND:165637, EU Trial Number: 2024-511259-16-00 
Sponsor Approval 
Date: 
24 March 2025 
 

 
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MIBG or PET; or positive bone marrow biopsy/aspirate in at least one site. If a patient 
has a history of bone marrow disease, bone marrow evaluations are required at baseline 
evaluation. If the results are negative, bone marrow aspirates or biopsies do not need to 
be repeated unless clinically indicated or for confirmation of complete remission (CR). 
9. 
Provision of archival tumor tissue (if adequate archival tumor tissue is not available, 
tumor tissue should be acquired by a fresh biopsy prior to enrollment).  
Note: If adequate archived tumor tissue is not available and/or a fresh biopsy cannot be 
safely performed, the participant may still be eligible with prior Sponsor approval. US 
only: Participants 12 to 17 years of age are not required to provide a biopsy.  
10. 
All participants’ tumors must have evidence of at least one of the following reported 
from a Clinical Laboratory Improvement Amendments (CLIA)‑certified or equivalent 
(ex-US) laboratory:  
• Gain or amplification of TRIM37, RAD51C, PPM1D, BRIP1, RNF43, or 
chromosome region 17q23 
• Overexpression of TRIM37 
• Genomically unaltered TP53 
• Other genomic profile with mechanistic rationale as agreed upon by the 
Investigator and Sponsor 
Note: For all participants, an anonymized/redacted Molecular Pathology report 
should be submitted to the Sponsor or designee during Pre-screening to confirm 
eligibility. For details, see the Molecular Eligibility Manual.   
11. 
Acceptable organ function at Screening, as evidenced by the following laboratory 
data: 
a. Creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation or institution 
standard formula.  
• 
US only: For participants 12 to 17 years of age, adequate renal function 
is defined as: calculated creatinine clearance by Cockcroft- Gault or 
institutional standard, including institutional formula specific for this age 
group. 
b. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or < 3.0 × ULN if known 
Gilbert’s disease. 
c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × 
ULN or ≤ 5.0 × ULN in the case of presence of liver metastases. 
d. Albumin > 2.0 g/dL 

 
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12. 
Acceptable hematologic function at Screening: 
a. No red blood cell (RBC) or platelet transfusions, and no myeloid, erythroid, or 
thrombopoietic growth factors within 7 days of the first dose of trial intervention 
b. Hemoglobin ≥ 9.5 g/dL except for participants with neuroblastoma with bone 
marrow involvement who are required to have hemoglobin ≥ 8.0 g/dL 
c. Absolute neutrophil count (ANC) ≥ 2000 cells/mm3 except for participants with 
neuroblastoma with bone marrow involvement who are required to have ANC ≥ 
1000 cells/mm3. Participants with neuroblastoma with bone marrow involvement 
are required to have ANC ≥ 750/uL. 
d. Platelet count ≥ 100,000 cells/mm3. Participants with neuroblastoma without bone 
marrow involvement are required to have platelet count ≥ 100,000 cells/mm3 
(transfusion independent, defined as not receiving platelet transfusions for at least 
7 days prior to enrollment). Participants with neuroblastoma with bone marrow 
involvement are required to have platelet count ≥ 75,000 cells/mm3 (transfusion 
independent, defined as not receiving platelet transfusions for at least 7 days prior 
to enrollment).  
13. 
Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at 
Screening.   
a. WOCBP is defined as fertile, following menarche and until becoming post-
menopausal unless permanently sterile. WOCBP, who are sexually active, and 
their partners must agree to use a highly effective form of contraception 
 
 throughout their participation in the trial and for 6 
months after the last dose of trial intervention. Female participants must refrain 
from donating eggs during their participation in the trial and for 6 months 
following last dose of trial intervention. 
b. Women are considered post-menopausal and not of childbearing potential if they 
have had no menses for 12 months without an alternative, potentially reversible 
medical cause or permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
14. 
Male participants with female partners of childbearing potential must follow a 
contraception method at least as conservative as Clinical Trial Facilitation Group 
(CTFG) recommendations 
during their participation in 
the trial for 6 months following last dose of trial intervention. Male participants must 
also refrain from donating sperm during their participation in the trial and for 6 
months following last dose of trial intervention. 

 
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15. 
For participants in the food effect portion of the trial, ability to consume a high-fat 
meal and fast for 12 hours. 
Exclusion Criteria:  
An individual who meets any of the following criteria will be excluded from participation in this 
trial: 
1. 
History or current condition (such as transfusion-dependent anemia, 
thrombocytopenia, or chronic neutropenia, except for participants with neuroblastoma 
with bone marrow involvement) or laboratory abnormality that in the opinion of the 
Investigator or Sponsor might pose a significant risk to participant safety, confound 
the trial results, or interfere with participation for the full duration of the trial 
treatment. 
2. 
Life-threatening illness, medical condition, active uncontrolled infection, or organ 
system dysfunction (such as coagulopathy or encephalopathy), or other reasons 
which, in the Investigator’s opinion, could compromise the participant’s safety, or 
interfere with or compromise the integrity of the trial outcomes. 
3. 
Uncontrolled, symptomatic brain metastases. Participants with previously treated 
brain metastases may participate provided the metastases are stable (without evidence 
of progression by imaging within 4 weeks prior to the first dose of trial intervention 
and any neurologic symptoms are controlled and stable), they have no evidence of 
new or enlarged brain metastases, and they are clinically stable and off steroids for at 
least 7 days prior to trial treatment. 
4. 
Presence of other known second malignancy with the exception of any cancer that has 
been in complete remission for ≥ 2 years or completely resected squamous and basal 
cell carcinomas of the skin. 
5. 
Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, 
hepatitis C virus (HCV), known human immunodeficiency virus (HIV), or acquired 
immunodeficiency syndrome (AIDS)-related illness. In equivocal cases, participants 
whose viral load is negative may be eligible. Eligibility criteria for HIV positive 
participants currently on highly active antiretroviral therapy (HAART) should be 
evaluated and discussed with the Medical Monitor and will be based on current and 
past CD4 and T-cell counts, history (if any) of AIDS‑defining conditions (e.g., 
opportunistic infections), and status of HIV treatment. 
6. 
Clinically significant vascular (both arterial and venous) and non‑vascular cardiac 
conditions, active or within 6 months prior to enrollment, including: 
a. 
Arterial disease such as cerebral vascular accident/stroke (including transient 
ischemic attack, myocardial infarction, and unstable angina) 
b. 
Venous diseases such as deep vein thrombosis and/or pulmonary embolism, 
central venous thrombosis 

 
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c. 
Non‑vascular cardiac disease such as congestive heart failure (New York Heart 
Association Classification Class ≥ 2) 
d. 
Conduction abnormality not controlled with pacemaker or medication 
e. 
Significant ventricular or supraventricular arrhythmias, including history of 
Torsades de pointes (TdP) unless all risk factors that contributed to TdP have 
been corrected. Participants with chronic rate-controlled atrial fibrillation in the 
absence of other cardiac abnormalities are eligible. 
f. 
Family history of sudden unexplained death or long electrocardiogram (ECG) 
interval measured from the onset of the QRS complex to the end of the T wave 
(QT syndrome) 
7. 
Mean resting QT interval corrected for heart rate (QTc) interval using the Fridericia 
formula (QTcF) > 470 msec (as calculated per institutional standards) demonstrated 
by at least 2 ECGs ≥ 1 minute apart at trial entry. 
8. 
Moderate or severe hepatic impairment (i.e., Child-Pugh class B or C). 
9. 
Uncontrolled hypertension (systolic blood pressure [BP] ≥ 160 mmHg and/or 
diastolic BP ≥ 100 mmHg) despite adequate treatment prior to first dose of treatment. 
10. 
Persistent Grade > 1 non-hematological toxicity from prior cancer therapy (except 
alopecia, anorexia or toxicity that is stable and poses no significant risk to the 
participant). Grade 2 peripheral neuropathy after documented treatment with taxanes 
and/or platinum-based therapy is allowed. 
11. 
Chemotherapy, small molecule or biologic antineoplastic agent given within 21 days 
or < 5 half‑lives, whichever is shorter, prior to first dose of trial intervention. For 
compounds for which 5 half‑lives is ≤ 21 days, a minimum of 10 days between 
termination of the prior treatment and administration of trial intervention is required. 
12. 
Other anticancer therapy (chemotherapy, immunotherapy, hormonal anticancer 
therapy, biological therapy, lanreotide/octreotide for neuroendocrine tumors 
(NETs)/neuroendocrine carcinomas (NECs), or other novel agent) while the 
participant is receiving trial intervention. For participants with breast or prostate 
cancer, continuation of long-term luteinizing hormone-releasing hormone (LHRH) or 
gonadotrophin releasing hormone (GnRH) are allowed if these medications were 
prescribed for at least 4 months before trial entry.  
13. 
Previously prescribed receptor activator of nuclear factor kappa B ligand (RANKL) 
inhibitor initiated less than 4 months prior to trial entry. Bisphosphonates are allowed 
if initiated/administered at least 28 days prior to enrollment. 
14. 
I-131 Meta-Iodo-Benzyl-Guanidine (MIGB) therapy within 6 weeks prior to initiation 
of trial treatment. 

 
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15. 
Prior treatment with a PLK4 inhibitor. 
16. 
Use of radiotherapy (except for palliative reasons) within 14 days prior to trial 
treatment initiation. 
17. 
Current treatment with medications that are known to prolong the QT interval 
. 
18. 
Participants who are receiving strong P-glycoprotein (P-gp) inhibitors and/or breast 
cancer resistance protein (BCRP) inhibitors within 14 days prior to first dose of trial 
intervention 
 
Note: RP-1664 is an in vitro inducer of CYP3A, CYP2B6, and CYP1A2. Investigators 
should consult with the Medical Monitor prior to enrollment of participants taking 
sensitive substrates of these enzymes, in particular CYP3A 
 
Participants must use additional methods of contraception if using 
estrogen/progestin-based agents. 
Note: RP-1664 is a substrate of CYP1A1. Literature examples of CYP1A1 inhibitors 
are limited and the existence of clinically relevant CYP1A1 inhibitors are also 
limited.  If investigators have questions with regards to particular concomitant 
medications, they should contact the Sponsor 
19. 
Major surgical procedures ≤ 28 days prior to trial treatment initiation, Participants 
must have recovered from any of the effects of any major surgery. No waiting period 
is required following central venous access placement, biopsy collection or minor 
surgeries as long as Investigator assesses the impact on trial participation. 
20. 
Gastrointestinal abnormalities, including inability to take whole, intact oral 
medication, requirement for intravenous alimentation, prior surgical procedures 
affecting absorption including total gastric resection or lap band, active inflammatory 
gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease, treatment 
for active peptic ulcer disease in the past 6 months, and malabsorption syndromes. 
21. 
Participants who are breastfeeding at screening or planning to become pregnant (self 
or partner) at any time during trial participation. 
22. 
Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol and/or follow-up procedures outlined in the protocol. 
Trial Interventions 
RP-1664 adolescent/adult whole capsules will be supplied as immediate-release solid dosage 
form for oral self-administration. The pediatric drug product for the Food Effect and PK 
Bridging portion of the trial will be supplied as sprinkle capsules.  

 
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Committees 
Independent Committees: SRC.