3-(2,6-DICHLOROPHENYL)-2,3-DIHYDRO-1-METHYL-7-[[3-METHYL-4-(1-METHYL-4-PIPERIDINYL)PHENYL]AMINO]-PYRIMIDO[4,5-D]PYRIMIDIN-4(1H)-ONE for Advanced solid tumours (CCNE1 amplification or deleterious mutations in FBXW7 or other proprietary gene)

Inclusion criteria

• {"criterion_text":"- Written informed consent and assent, according to local guidelines, signed and dated by the participating patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses."}
• {"criterion_text":"- Ability to comply with the protocol and study procedures detailed in the Schedule of Assessments."}
• {"criterion_text":"- Ability to swallow and retain tablets and capsules whole and intact."}
• {"criterion_text":"- Acceptable organ function at Screening, as evidenced by the following laboratory data: a. For Module 1: Creatinine clearance ≥60 mL/min calculated using the Cockcroft-Gault equation. For Module 2 and 3: Creatinine clearance ≥45 mL/min calculated using the Cockcroft-Gault equation or measured by 24-hour urine collection. Module 4: Creatinine clearance ≥60 mL/min calculated using the Cockcroft-Gault equation or measured by 24-hour urine collection. b. Total bilirubin ≤1.5 × ULN or <3.0 × ULN if known Gilbert's disease c. Serum albumin ≥2.5 g/dL d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × ULN or ≤ 5.0 × ULN in the case of presence of liver metastases"}
• {"criterion_text":"- Acceptable hematologic function at Screening: a. No red blood cell (RBC) or platelet transfusions or growth factors within 7 days of the first dose of lunresertib (For Module 1). For Module 2, 3 and 4: No red blood cell (RBC) or platelet transfusions or growth factors within 14 days of the first dose of the study drug b. Hemoglobin ≥9.0 g/dL, except if anemia is due to potentially reversible and manageable etiology (e.g., bleeding from tumor lesion), after discussion with and approval by the Medical Monitor c. ANC ≥1500 cells/mm3 d. Platelet count ≥100,000 cells/mm3"}
• {"criterion_text":"- Negative pregnancy test (serum) for women of childbearing potential at Screening and prior to the first dose of study drug.."}
• {"criterion_text":"- Male patients with female partners of childbearing potential must follow a contraception method (oral contraceptives allowed) during their participation in the study for 6 months following last dose of drug. Male patients must also refrain from donating sperm during their participation in the study and for 6 months following last dose of study drug."}
• {"criterion_text":"- Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except for neuropathy, hypothyroidism requiring medication, and alopecia, which must have resolved to Grade ≤2)."}
• {"criterion_text":"- Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment."}
• {"criterion_text":"- Life expectancy ≥12 weeks after the start of the treatment according to the investigator's judgment."}
• {"criterion_text":"- Additional Inclusion Criteria for Module 1c and module 3: Ability to consume a high-fat meal and fast for 12 hours. Module 1c will only be open to patients ≥18 years-of-age."}
• {"criterion_text":"- Male or female and ≥12 years-of-age at the time of signature of the informed consent form (ICF). Patients 12 to 17 years-of-age will be enrolled only after at least 4 patients ≥18 years-of-age have completed 1 cycle of therapy."}
• {"criterion_text":"- Lansky performance status ≥50 for patients ≤16 years of age, or ECOG score of 0, 1, or 2 (module 1) and for Module 2,3 and 4 ECOG 0 or 1."}
• {"criterion_text":"- All patients must have locally advanced or metastatic resistant or refractory solid tumors. Patients <18 years-of-age will be eligible only if standard or available curative therapy does not exist. Patients ≥18 years-of-age are eligible if, in the opinion of the investigator, the patient is not a candidate for, or would be unlikely to tolerate or derive significant clinical benefit from, appropriate standard-of-care therapy, or if the patient declines standard-of-care therapy. For Module 4b only, patients must: a. Have high-grade serous ovarian, fallopian tube or peritoneal cancer b. Have been previously treated with bevacizumab (if indicated) c. Have completed at least 1 but no more than 3 prior lines of therapy for advanced or metastatic cancer: - Neoadjuvant, adjuvant, and the combination of both will be considered as one line of therapy. - Treatment with bevacizumab or PARPi given as monotherapy or in combination as maintenance therapy is allowed and not counted as a separate line of therapy. - The use of single-agent hormonal therapy given for reasons other than progressive disease per RECIST v1.1 (i.e., hormonal therapy given for increasing CA-125 levels) is not counted as a separate line of therapy."}
• {"criterion_text":"- Patients <18 years of age must weigh at least 40 kg."}
• {"criterion_text":"- Archived tumor tissue sample available or lesion that can be safely biopsied if the archival sample is not available."}
• {"criterion_text":"- All patient's tumors, except for types of endometrial cancer listed in criteria #8, must have evidence of at least one of the following as reported by a local CLIA-certified or equivalent (ex-United States [US]) laboratory and centrally confirmed by PODS: a. CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH b. FBXW7 deleterious mutations identified by either a tumor or plasma NGS test c. Proprietary gene deleterious mutations identified by either a tumor or plasma NGS test d. For backfill cohorts, tumors with other genes with mechanistic rationale agreed upon between the Sponsor and Investigator will be accepted (not applicable for Module 4). Module 4b will enroll patients with: a. CCNE1 amplification (non-equivocal) as determined by either a tumor or plasma NGS test, or FISH"}
• {"criterion_text":"- The following types of endometrial cancer are eligible a. Serous endometrial cancer (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided) b. Carcinosarcoma of the endometrium c. Grade 3 endometrioid and undifferentiated carcinoma (p53 IHC must be confirmed to be aberrant or local NGS report confirming TP53 loss of function mutation must be provided; MMR IHC must be retained and/or tumor must be MSS; polymerase epsilon (POLE) hypermutated type must be excluded)"}
• {"criterion_text":"- Measurable disease as per RECIST v1.1."}

Exclusion criteria

• {"criterion_text":"- Chemotherapy or small molecule antineoplastic agent given within 21 days or <5 half-lives, whichever is shorter, prior to first dose of study drug. For drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the prior treatment and administration of study drug treatment is required. For patients with breast or prostate cancer, continuation of long-term luteinizing hormone-releasing hormone (LHRH), gonadotrophin releasing hormone (GnRH) is permitted, or previously prescribed Receptor Activator of Nuclear Factor kB Ligand (RANKL) inhibitor are allowed if these medications were prescribed for at least 3 months before trial entry. Bisphosphonates are allowed if previously prescribed at least 28 days prior to enrollment."}
• {"criterion_text":"- Patients who are pregnant or breastfeeding."}
• {"criterion_text":"- Module 1: Known sensitivity to any of the ingredients of lunresertib. Module 2 and 3: Known hypersensitivity to any of the ingredients of lunresertib or RP-3500. Module 4: Known hypersensitivity to any of the ingredients of lunresertib or Debio 0123."}
• {"criterion_text":"- Patient who are unable to swallow ablets and capsules whole and intact."}
• {"criterion_text":"- Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites requiring drainage within 4 weeks prior to enrollment, coagulopathy, or encephalopathy), or other reasons which, in the investigator's opinion, could compromise the participating patient's safety, or interfere with or compromise the integrity of the study outcomes."}
• {"criterion_text":"- Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of study drug"}
• {"criterion_text":"- Additional exclusion criteria for Module 2 and 3: Prior therapy with an ATR, DNA-PK, PKMYT1, or WEE1 inhibitor."}
• {"criterion_text":"- Uncontrolled hypertension (systolic blood pressure [BP] ≥160 mmHg; diastolic BP ≥100 mmHg) despite adequate treatment prior to first dose of Study drug ."}
• {"criterion_text":"- Additional exclusion criteria for Module 4: Prior therapy with a PKMYT1 or WEE1 inhibitor."}
• {"criterion_text":"- Additional exclusion criteria for Module 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."}
• {"criterion_text":"- Additional exclusion criteria for Module 4: Clinically significant gastrointestinal abnormality that would affect the absorption of drugs, such as malabsorption syndrome, major resection of the small bowel, total gastrectomy, or inflammatory bowel disease."}
• {"criterion_text":"- Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness. In equivocal cases, patients whose viral load is negative, may be eligible. HIV seropositive patients who are healthy and low risk for AIDSrelated outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed with the sponsor's 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"}
• {"criterion_text":"- Additional exclusion criteria for Module 4: Mean resting QT interval corrected for heart rate (QTc) interval using the Fridericia formula (QTcF) >450 msec (as calculated per institutional standards) obtained from 3 ECGs ≥1 minute apart at study entry."}
• {"criterion_text":"- Additional exclusion criteria for Module 4: Patients who are receiving a drug or herbal product that is a mild, moderate, or strong inhibitor of CYP3A4 or a strong inhibitor of CYP2D6 within at least 5 half-lives of the drug prior to first dose of study drug"}
• {"criterion_text":"- Additional exclusion criteria for Module 4:Patients who are receiving a drug or herbal product that is a mild, moderate, or strong inducer of CYP3A within 28 days prior to first dose of study drug"}
• {"criterion_text":"- Additional exclusion criteria for Module 4: Current treatment with medications that are well-known to prolong the QT interval or with known risk of TdP (Appendix 2). If patients are on these medications, a wash-out period of at least 5 half-lives is needed prior to receiving the treatment."}
• {"criterion_text":"- Additional exclusion criteria for Module 4: Unable to avoid exposure to high levels of UV radiation."}
• {"criterion_text":"- Additional exclusion criteria for Module 4: Immunization with live or live-attenuated vaccine within 28 days prior to study inclusion or planned injection of live or live-attenuated vaccine."}
• {"criterion_text":"- Moderate or severe hepatic impairment (i.e., Child-Pugh class B or C)."}
• {"criterion_text":"- Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart AssoClass 2: a. Unstable angina pectoris b. Congestive heart failure c. Acute myocardial infarction d. Conducciation (NYHA) ≥tion abnormality not controlled with pacemaker or medication e. Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible) f. Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or sudden death from cardiac-related causes before the age of 50, or long ECG interval measured from the onset of the QRS complex to the end of the T wave (QT) syndrome"}
• {"criterion_text":"- Mean resting QT interval corrected for heart rate (QTc) interval using the Fridericia formula (QTcF) >450 msec/male and >470 msec/female (as calculated per institutional standards) obtained from 3 ECGs >1 minute apart at study entry."}
• {"criterion_text":"- Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol"}
• {"criterion_text":"- For Module 1: Patients who are receiving strong CYP3A inhibitors or inducers or proton pump inhibitors within 14 days prior to first dose of study drug. For Module 2 and 3 : Patients who are receiving strong CYP3A inhibitors or inducers or proton pump inhibitors and P-gp inhibitors and/or BCRP inhibitors within 14 days prior to first dose of study drug"}
• {"criterion_text":"- Uncontrolled, symptomatic brain metastases. Patients with previously treated brain metastases may participate provided the metastases are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms are controlled and stable), have no evidence of new or enlarged brain metastases, and are clinically stable and off steroids for at least 7 days prior to study drug. For Additonally for Module 2, 3 and 4: Patients with leptomeningeal disease are excluded without exception."}
• {"criterion_text":"- History or current condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results, or interfere with the patient's participation for the full duration of the study treatment."}

Primary endpoints

• {"endpoint_text":"- Incidence and severity of treatment-emergent adverse events (TEAEs), laboratory assessments, vital signs, electrocardiograms (ECGs), and use of concomitant medications.","definition_or_measurement_approach":"Safety will be assessed by reporting incidence and severity of TEAEs, safety laboratory assessments, vital sign measurements, ECGs, and concomitant medication use."}
• {"endpoint_text":"- Dose-limiting toxicities (DLTs)","definition_or_measurement_approach":"DLTs will be assessed per protocol-defined toxicity criteria during dose-escalation periods to determine MTD."}
• {"endpoint_text":"- Module 2: Treatment-emergent adverse events (TEAEs), physical examinations (PEs), safety laboratory assessments, electrocardiograms (ECGs), and vital sign measurements","definition_or_measurement_approach":"Safety assessments as above for combination module (lunresertib + RP-3500)."}
• {"endpoint_text":"- Module 2: DoseFor MTD: incidence of dose-limiting toxicities (DLTs) For RP2D: incidence and severity of cumulative safety data","definition_or_measurement_approach":"For Module 2, incidence of DLTs will determine MTD; cumulative safety data inform recommended Phase 2 dose (RP2D)."}
• {"endpoint_text":"- Module 3: Plasma concentrations of lunresertib with calculation of Cmax, Tmax, AUC, elimination t1/2, and other PK parameters as appropriate","definition_or_measurement_approach":"Pharmacokinetic sampling with calculation of PK parameters Cmax, Tmax, AUC, t1/2 and other relevant PK measures."}
• {"endpoint_text":"- Module 3: DLTs, TEAEs, safety laboratory assessments For MTD: incidence of DLTs For RP2D: incidence and severity of cumulative safety data","definition_or_measurement_approach":"Safety and DLT assessment to determine MTD and RP2D in Module 3; standard safety monitoring."}
• {"endpoint_text":"- Module 4: Treatment-emergent adverse events (TEAEs), physical examinations (PEs), safety laboratory assessments, electrocardiograms (ECGs), and vital sign measurements","definition_or_measurement_approach":"Safety monitoring as above for lunresertib + Debio 0123 combination."}
• {"endpoint_text":"- Module 4: For MTD: incidence of Dose limiting toxicities (DLTs) For RP2D: incidence and severity of cumulative safety data","definition_or_measurement_approach":"DLT incidence used to define MTD; cumulative safety data used to determine RP2D."}
• {"endpoint_text":"- Module 4: Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS","definition_or_measurement_approach":"Tumor response evaluated by RECIST v1.1 (best percent change from baseline, objective response rate, duration of response, clinical benefit rate, tumor marker responses, progression-free survival)."}

Secondary endpoints

• {"endpoint_text":"- Module 1: • Plasma concentrations of lunresertib with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination t1/2, and other parameters as appropriate","definition_or_measurement_approach":"PK sampling and calculation of Cmax, Tmax, Cmin, AUC, t1/2 and other PK parameters."}
• {"endpoint_text":"- Module 1: Assessment of biomarkers (e.g., g-H2AX, p-CDK1 Thr14) in pre- and on-treatment biopsies, and circulating tumor DNA (ctDNA) dynamics during treatment.","definition_or_measurement_approach":"Pharmacodynamic biomarker assays on pre- and on-treatment biopsies and ctDNA monitoring."}
• {"endpoint_text":"- Module 1: Best percent change in tumor size from baseline, objective response rate (ORR), overall response rate, tumor marker response, duration of response (DOR), clinical benefit rate (CBR), available progression-free survival (PFS)","definition_or_measurement_approach":"Tumor response assessments per RECIST v1.1 and other clinical outcome measures (ORR, DOR, CBR, PFS)."}
• {"endpoint_text":"- Module 2: • Plasma concentrations of lunresertib and RP-3500 with calculation of maximum observed plasma concentration (Cmax), time to maximum observed plasma concentration (Tmax), minimum observed plasma concentration (Cmin), area under the plasma concentration-time curve (AUC), elimination t1/2, and other parameters as appropriate.","definition_or_measurement_approach":"PK sampling for both agents with calculation of standard PK parameters."}
• {"endpoint_text":"- Module 2: Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response; PFS","definition_or_measurement_approach":"Tumor response and clinical efficacy measures per RECIST v1.1."}
• {"endpoint_text":"- Module 3: TEAEs, safety laboratory assessments Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS Module 3c (if needed) To further characterize the PK of lunresertib tablets and assess preliminary anti-tumor effect.","definition_or_measurement_approach":"Safety monitoring and tumor response assessments; PK characterization for tablet formulation if Module 3c performed."}
• {"endpoint_text":"- Module 3: Plasma concentrations of lunresertib with calculation of Cmax, Tmax, AUC, elimination t1/2, and other PK parameters as appropriate Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS","definition_or_measurement_approach":"PK and tumor response assessments as described."}
• {"endpoint_text":"- Module 4; Best percent change in tumor size from baseline, ORR, overall response rate, DOR, CBR, tumor marker response, PFS","definition_or_measurement_approach":"Tumor response and clinical outcome measures per RECIST v1.1."}
• {"endpoint_text":"- Module 4: Plasma concentrations of lunresertib and Debio 0123 with calculation of Cmax, Tmax, Cmin, AUC, elimination t1/2, and other parameters as appropriate","definition_or_measurement_approach":"PK sampling for lunresertib and Debio 0123 with calculation of PK parameters."}
• {"endpoint_text":"- Module 4: Assessment of biomarkers (e.g., γ-H2AX, p-CDK1 Thr14, pCDK1 Tyr15) in pre- and on-treatment biopsies, and ctDNA dynamics during treatment","definition_or_measurement_approach":"Pharmacodynamic biomarker evaluation on tissue biopsies and ctDNA assays."}

Denmark

Earliest CTIS Part Ii Submission Date

01-03-2024

Latest Decision Or Authorization Date

12-03-2024

Processing Time Days

11

Number Of Sites

1

Number Of Participants

20

Spain

Earliest CTIS Part Ii Submission Date

23-09-2024

Latest Decision Or Authorization Date

30-09-2024

Processing Time Days

7

Number Of Sites

1

Number Of Participants

10

Netherlands

Earliest CTIS Part Ii Submission Date

09-10-2024

Latest Decision Or Authorization Date

21-10-2024

Processing Time Days

12

Number Of Sites

1

Number Of Participants

8

Primary sponsor

Full Name

Debiopharm International S.A.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Propharma Group LLC

Responsibilities

Site management

Name

Bioagilytix Labs LLC

Responsibilities

PK bioanalytical analysis

Name

Labconnect LLC

Responsibilities

Collection kits, shipping logistics, ctDNA samples/back-up PK/Frozen biopsy sample accessioning and short term storage

Name

Precision For Medicine Inc.

Responsibilities

information repository, sample reconciliation and query tracker system

Name

Navitas LLP

Responsibilities

PV vendor

Name

Azenta Germany GmbH

Responsibilities

Longterm storage of biosamples

Third parties

• {"country":"United States","full_name":"Propharma Group LLC","duties_or_roles":"Site management","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"PK bioanalytical analysis","organisation_type":"Pharmaceutical company"}
• {"country":"India","full_name":"Navitas LLP","duties_or_roles":"PV vendor","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Mosaic Laboratories LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"Longterm storage of biosamples","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labconnect LLC","duties_or_roles":"Collection kits, shipping logistics, ctDNA samples/back-up PK/Frozen biopsy sample accessioning and short term storage","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"The University Of Texas MD Anderson Cancer Center","duties_or_roles":"Eligibility Confirmation","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Lanterne Dx LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Xerimis B.V.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Precision For Medicine Inc.","duties_or_roles":"information repository, sample reconciliation and query tracker system","organisation_type":"Pharmaceutical company"}