E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory primary CNS lymphoma (PCNSL) |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed or refractory primary central nervous system lymphoma |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036685 |
E.1.2 | Term | Primary central nervous system lymphoma |
E.1.2 | System Organ Class | 100000013303 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the clinical efficacy of PQR309 in the treatment of patients with relapsed or refractory primary CNS lymphoma. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate:
- Overall safety and tolerability of PQR309
- Overall clinical efficacy of PQR309
- Pharmacokinetics (PK) of PQR309 in plasma |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. ≥ 18 years of age.
2. Patient with histologically/cytologically confirmed PCNSL at first progression.
3. Relapsed or refractory PCNSL demonstrated by cranial MRI.
4. Presence of at least one lesion of bi-dimensionally measurable disease on baseline MRI with a contrast-enhancing tumor of at least 1 cm (10 mm) in the longest diameter.
5. Maximum two prior systemic therapy regimens excluding myeloablative therapy at first relapse.
6. If receiving corticosteroids, patients must have been on a stable or decreasing dose of corticosteroids and no more than 8 mg dexamethasone (or equivalent) for at least 5 days prior to date of enrollment.
7. Karnofsky Performance Score (KPS) ≥ 70%.
8. More than 4 weeks from any investigational agent (at the judgment of the investigator and in agreement with lead investigator and PIQUR).
9. Adequate haematological, liver and renal function defined as follows: absolute neutrophil count (ANC) ≥ 1.5x10^9/l, platelets ≥ 100x10^9/l, hemoglobin ≥ 100g/L. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN. Serum Creatinine ≤ 1.5 times ULN.
10. Able and willing to swallow and retain oral medication.
11. Female and male patients of reproductive potential must agree to use effective contraception from screening until 90 days after discontinuing study treatment.
12. Willing and able to sign the informed consent and to comply with the protocol for the duration of the study. |
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E.4 | Principal exclusion criteria |
1. Secondary CNS lymphoma or chronic immunosuppresion-associated CNS lymphoma.
2. Previous allogeneic hematopoietic stem cell transplant (HSCT transplant).
3. Patients with persisting symptoms from previous whole brain radiotherapy (WBRT).
4. Other concomitant anti-tumor therapy as determined by the study team.
5. Patients unable to undergo contrast-enhanced MRI.
6. Prior treatment with a PI3K inhibitor, AKT inhibitor, or mTOR inhibitor.
7. Patient is currently using herbal preparations or medications. Patient should stop using herbal medications 7 days prior to the first dose of the study drug.
8. Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders.
9. Anxiety ≥CTC AE grade 3.
10. Patient has an uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, known HIV infection, chronic liver disease, chronic renal disease, pancreatitis, chronic pulmonary disease, active cardiac disease or cardiac dysfunction, interstitial lung disease, active autoimmune disease, uncontrolled diabetes, neuropsychiatric or social situations that would limit compliance with the study requirements.
11. Presence of gastrointestinal disease or any other condition that could interfere significantly with the absorption of the study drug.
12. Concomitant treatment with medicinal products that increase the pH (reduce acidity) of the upper gastrointestinal tract, including, but not limited to, proton-pump inhibitors (e.g. omeprazole), H2-antagonists (e.g. ranitidine) and antacids is restricted. Patients may be enrolled in the study after a washout period sufficient to terminate their effect.Patients who require treatment to increase the pH of the upper GI tract can be treated with 300mg ranitidine given once daily at bed-time. Importantly, in this case PQR309 dosing is switched to the early evening. Patients will take PQR309 on an empty stomach approx 4 hours after lunch and remain fasted for an additional 2 hours prior to the evening meal.
13. Patient has a history of invasive malignancy other than PCNSL. Patients are eligible if they are disease free for at least 3 years and deemed to be at low risk for recurrence by the Investigator. Patients diagnosed with cervical cancer in situ, basal cell or squamous cell carcinoma of the skin and treated within the past 3 years are eligible.
14. Women who are pregnant or breast feeding.
15. Women able to conceive and unwilling to practice an effective method of birth control from screening until 90 days after discontinuing study treatment (women of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose of PQR309).
16. Fasting glucose > 7.0 mmol/L (126 mg/dL). |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR including complete response (CR), unconfirmed complete (CRu) and partial response (PR) according to the 2005 Response Criteria of the International Primary CNS Lymphoma Collaborative Group (IPCG) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
4 and 8 weeks after first intake of PQR309, subsequently every 8 weeks |
|
E.5.2 | Secondary end point(s) |
Safety:
- Incidence and severity of AEs including SAEs
- Changes in vital signs (pulse rate, blood pressure, body temperature), Karnofsky performance status (KPS), physical examinations, body weight, ECG, PHQ-9 questionnaire and GAD-7 mood scale score
- Changes of routine laboratory assessments (haematology, blood chemistry, urinalysis)
- Changes in Mini-Mental State Examination (MMSE) score
Additional Clinical Efficacy:
- Time to response (TTR), duration of response (DOR), time to treatment failure (TTF), progression-free survival (PFS) and survival rate at 1 year
Pharmacokinetics:
- PQR309 plasma concentration, PK parameters |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
AE monitoring: continuously until 30 days after the last dose
Vital signs, physical examination: at Screening, at Weeks 1, 2, 3, 4 and 7 (and every three weeks later), at the end of treatment and 30 days after the last dose
PHQ-9 and GAD-7: at Screening, Week 4 and 7 (and every 3 weeks later), and end of treatment
Haematology & Blood chemistry: at Screening, at Weeks 1, 2, 3, 4, 6 and 7 (and every three weeks later), at the end of treatment, and 30 days after the last dose
Urinalysis: at Screening, at Weeks 1, 4 and 7 (and every three weeks later), and end of treatment
MMSE: at Screening and end of treatment
PK sampling: at Weeks 1 (Day 1 and 2), 2, 3, 4 and 7 until Day 64 (exact timepoints depend on dosing schedule) |
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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 | No |
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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Germany |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 23 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |