E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Tumour Agnostic treatment. ● Module differentiation: – Module 1 - monotherapy – solid tumour patients with cancer types that are enriched for HRD/FAD defects – Module 2 – combination with Carboplatin – solid tumour patients with cancer types that are enriched for HRD/FAD defects – Module 3 – combination with SOC ICI– solid tumour patients with oligoprogressive disease receiving immune-checkpoint inhibitor (ICI) as standard of care
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E.1.1.1 | Medical condition in easily understood language |
Patients with a solid cancer that has particular genetic mutations which makes it particularly sensitive to CP-506. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10084788 |
E.1.2 | Term | HRD positive advanced ovarian cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033604 |
E.1.2 | Term | Pancreatic cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067821 |
E.1.2 | Term | Head and neck cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033128 |
E.1.2 | Term | Ovarian cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060862 |
E.1.2 | Term | Prostate cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1.Incidence of treatment-emergent adverse events including dose-limiting toxicities The proportion of patients with treatment-emergent (serious) adverse events including dose-limiting toxicity (DLT)
[Time Frame: Baseline until 60 days after last administration of CP-506]
2.Incidence of clinically significant abnormal measurements in physical examination, vital signs, electrocardiogram (ECG), lab tests and ECOG performance status Physical examination; vital signs; electrocardiogram (ECG); haematology; clinical chemistry; urinalysis; plasma/renal makers; tumour markers; ECOG performance status
[Time Frame: Baseline until 60 days after last administration of CP-506] |
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E.2.2 | Secondary objectives of the trial |
Characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) Measurement of CP-506 levels in plasma over time to calculate Cmax. AUC of CP-506 plasma concentration [Time Frame: Before administration of CP-506 up to day 4 after initial treatment on cycle 1] Determine the minimal biological effective dose Dose that results in 1) a decrease of 20% of hypoxia radiomics score on sequential CT of at least one lesion OR 2) a decrease of 20% of the initial tumour volume of at least one lesion [Time Frame: Baseline until 60 days after last administration of CP-506]
Efficacy of CP-506 (RECIST) using automated volumetric analysis of all the measurable lesions (aRECIST): Time to response Duration of response - the time from documentation of tumour response to disease progression Assessment of stabilization of disease, using waterfall plots. DRR will be combined with stable disease (SD) to produce a DCR Overall survival |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria:
Male or female, aged 18 years or more at the time of signing the informed consent Be willing and able to provide written informed consent for the trial Life expectancy of at least 6 months Be willing to have a biopsy collection procedure ECOG Performance status <= 2 Must have adequate organ and bone marrow function, defined as the following:
6.1. ANC ≥ 1500 µL 6.2. Hemoglobin ≥ 9.0 g/dL 6.3. Platelets ≥ 100 000 µL 6.4. Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5 × ULN 6.5. AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases) 6.6. Creatinine ≤ 1.5 × ULN 6.7. Coagulation: INR ≤ 1.5 × ULN (or within therapeutic ranges for participants on anticoagulant treatment)
Measurable disease on CT scan (RECIST 1.1) If female, not pregnant, not breastfeeding, and at least one of the following conditions applies:
8.1. Not a woman of childbearing potential (WOCBP) 8.2. A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 4 weeks after the last dose of study treatment and shows a negative pregnancy test before the start of the treatment
If male, must agree to use contraception during the treatment period and for at least 4 weeks after the last dose of study treatment Able and willing to comply with the protocol Module 1 - monotherapy Have histologically or cytologically-confirmed advanced or metastatic solid tumour for whom no standard of care or known effective treatment options are available Have indications of Homologous Recombination (HR) or Fanconi Anaemia (FA) DNA damage repair defects, based on hereditary cancer diagnostics (e.g. BRCA1/2 carriers), dedicated HRD genomic assays (including exome-sequencing) from liquid or tissue biopsies. Presence of such a defect must have been established via a tissue based next generation sequencing test, performed --in a CAP/CLIAcertified (or comparable local or regional certification) laboratory, or via a germline test from one of the following approved providers: Myriad Genetics; Invitae; Ambry; Quest; Color Genomics; MSKCC-IMPACT; GeneDx; Foundation Medicine OR Have cancers with an increased incidence of HRD/FAD: ovarian (41%), breast (18%), pancreas (10%), prostate (9%), and head and neck (5%) OR Patients who were previously responsive to alkylating agent (Partial Response/Complete Response according to RECIST criteria).
Module 2 - Carboplatin combination
Patient must be eligible to carboplatin treatment. Have histologically or cytologically-confirmed advanced or metastatic solid tumour for whom no standard of care or known effective treatment options are available. Have indications of Homologous Recombination (HR) or Fanconi Anaemia (FA) DNA damage repair defects based on hereditary cancer diagnostics (e.g. BRCA1/2 carriers), dedicated HRD genomic assays (including exome-sequencing) from liquid or tissue biopsies; or have cancers with an increased incidence of HRD/FAD: ovarian (41%), breast (18%), pancreas (10%), prostate (9%), and head and neck (5%) or patients who were previously responsive to alkylating agent (Partial Response/Complete Response according to RECIST criteria) but the treatment has been discontinued due to toxicity.
Module 3 - ICI combination
Have histologically or cytologically-confirmed advanced or metastatic solid tumour Receiving immune checkpoint inhibitor (ICI) monotherapy as standard of care for at least 6 months prior to the beginning of the study and who are oligoprogressive. Oligoprogression disease is defined as localized treatment failure at one or two anatomic sites, with one to five progressive and measurable (according to RECIST 1.1) lesions, either new or with ≥ 20% growth of their longest diameter (short-axis in lymph nodes), while other tumor manifestations could shrink or grow less than 20% in diameter |
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E.4 | Principal exclusion criteria |
Core:
Prior radiotherapy to more than 25% of bone marrow Not recovered from all acute toxic effects of prior anticancer therapy (excluding CTCAE Grade 1 alopecia or peripheral neuropathy) Patients with significant cardiac co-morbidity, such as NYHA Class III or IV CHF, unstable angina, MI within the previous 6 months, or ventricular arrhythmias requiring drug therapy, pacemaker or implanted defibrillator. Serious, uncontrolled cardiac arrhythmia or clinically significant electrocardiogram abnormalities including second degree (Type II) or third-degree atrioventricular block. This does not apply to patient with a pace maker. Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting or bypass grafting. Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association functional classification system. Symptomatic pericarditis A marked baseline prolongation of QT/QTc interval (> 450 ms) History of risk factors for Torsade de Pointe (e.g. heart failure, hypokalemia, family history of Long QT syndrome) Use of concomitant medication prolonging the QT/QTc interval Evidence of uncontrolled infection or infection requiring a concomitant parenteral antibiotic Evidence of any other significant clinical disorder or laboratory finding Patients with a diagnosis (or strong suspicion) of a rare genetic disorder related to germline biallelic HR/FA and DNA repair gene mutations, such as Fanconi anemia patients of any subtype, Ataxia telangiectasia, Xeroderma pigmentosum, Cockayne, Nijmegen breakage, Werner and Bloom syndrome patients Patient or physician plans concomitant chemotherapy, radiation therapy, hormonal and/or biological treatment for cancer including immunotherapy while on study Patient has been treated with any investigational drug or investigational therapeutic device within 30 days (60 days in case of biological compound) of initiating study treatment Less than 4 weeks since prior major surgery Known positive for HIV, Hepatitis B surface antigen positive or Hepatitis C positive with abnormal liver function tests Known allergy to alkylating agents Central nervous system (CNS) metastases, with the following exception: Participants with asymptomatic CNS metastases who are clinically stable and have no requirement for steroids for at least 14 days prior to randomization. Invasive malignancy or history of invasive malignancy other than disease under study within the last 3 years, except as noted below: Autoimmune disease (current or history; refer to Table 19) or syndrome that required systemic treatment within the past 2 years Has a diagnosis of immunodeficiency or is receiving systemic steroids (>10 mg oral prednisone per day or equivalent) or other immunosuppressive agents within 7 days prior to randomization Note: Receipt of any live vaccine within 30 days prior randomization Prior allogeneic/autologous bone marrow or solid organ transplantation Has current pneumonitis or history of non-infectious pneumonitis that required steroids or other immunosuppressive agents Recent history (within the past 6 months) of uncontrolled symptomatic ascites, pleural or pericardial effusions Recent history (within the past 6 months) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intraabdominal abscess Recent history of allergen desensitization therapy within 4 weeks of randomization Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice. Note: Stable non-cirrhotic, chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria Known history of active tuberculosis Any psychiatric disorder, or other condition that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures in the opinion of the investigator
Module 1 - monotherapy Patients who have received anticancer therapy (including radiotherapy) within 4 weeks of inclusion
Module 2 - Carboplatin combination Patients who have received anticancer therapy (including radiotherapy) within 4 weeks of inclusion with exclusion of carboplatin.
Module 3 - ICI combination
Patients who have received anticancer therapy (including radiotherapy) within 4 weeks of inclusion with exception of ICI Patients progressive under ICI justifying the immediate discontinuation of ICI Patients who would not receive further treatment with ICI as standard of care Patients with Complete Response under ICI |
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E.5 End points |
E.5.1 | Primary end point(s) |
15.1 SAFETY ENDPOINTS The following safety parameters will be assessed: • Physical examination, vital signs, and ECOG performance status • 12-lead ECG • Laboratory parameters: Haematology, coagulation, clinical chemistry, serum renal markers, urinalysis, urine renal markers, and tumour markers (patients with relevant tumour types) • Number of DLTs • AEs (graded by (88)) (including pregnancy) • Number of withdrawals, discontinuations and dose reductions |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1, 2, 3, 4, 14, 22, 23, 24, 25, 35, 43, 44, 45, 46, 57, 64, 105 |
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E.5.2 | Secondary end point(s) |
14.1 EFFICACY ENDPOINTS Efficacy Endpoints for Part A and Part B: - Tumour response defined as: • Partial or Complete Response (RECIST 1.1), providing Objective Response Rate (ORR), Durable Response Rate (DRR) and Overall Survival (OS) Pharmacokinetic Endpoints - Module 1A - MBED: Minimal biological effective dose will be measured by CT scan. It corresponds to the dose that results in 1) a decrease of 20% of hypoxia radiomics score on sequential CT of at least one lesion OR 2) a decrease of 20% of the initial tumour volume of at least one lesion. - Dose linearity of PK parameters for doses up to and beyond MBED Pharmacodynamic Endpoints - Tumour tissue Proof of Principle • Reduction of tumor lesion hypoxic fraction. • Reduction of tumor lesion size.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1, 2, 3, 4, 14, 22, 25, 35, 43, 46, 57, 64, 105 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
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E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |