| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer (NSCLC), colorectal cancer
(CRC), and other solid tumors. |
| Μη μικροκυτταρικός καρκίνος του πνεύμονα (ΜΜΚΠ), καρκίνος παχέος εντέρου και ορθού (ΚΠΕ-Ο) και άλλοι συμπαγείς όγκοι |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer, colorectal cancer and other solid tumors. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Monotherapy Part:
•To assess the PK of selinexor after a single dose of 40 mg (2 × 20 mg) among patients with moderate and severe hepatic impairment relative to 100 mg (5 × 20 mg) among patients with normal hepatic function.
Combination Therapy Part: Arm A:
•To assess the preliminary anti-tumor activity of selinexor in combination with docetaxel in patients with NSCLC.
Combination Therapy Part: Arm C
•To assess the safety and tolerability of QW vs BIW selinexor in combination with FOLFIRI in patients with CRC.
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| E.2.2 | Secondary objectives of the trial |
Monotherapy
To assess the tolerability of Selinexor as monotherapy in patients with any type of advanced or metastatic solid tumor indication and moderate or severe hepatic impairment.
Combination Therapy Part: Arm A
To assess preliminary anti-tumor activity, safety and tolerability of selinexor in combination with docetaxel in patients with NSCLC.
Combination Therapy Part: Arm C
To assess the preliminary anti-tumor activity of selinexor in combination with FOLFIRI in patients with CRC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Common inclusion criteria for all patients:
1. Are ≥18 years of age.
2. Have histologically confirmed solid tumor (any type of advanced or metastatic solid tumor for the Hepatic Impairment Arm of the Monotherapy Part), advanced or metastatic NSCLC or CRC and evidence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
3. Willing to provide signed written informed consent in accordance with federal, local, and institutional guidelines and comply with all requirements of the study.
4. Female patients of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective (dual methods of) contraception throughout the study and for 4 months following the last dose of study drug; and male patients must use an effective barrier method of contraception throughout the study and for 4 months following the last dose of study drug if sexually active.
For the Monotherapy Part only:
5. Have received at least 1 line of systemic anticancer treatment unless there is no first-line standard of care therapy or standard of care therapy is contraindicated adjuvant or neoadjuvant therapy is not counted as one line of systemic therapy). Patients must have failed prior standard curative therapy for their disease, must be intolerant to or be ineligible for any potentially curative approved treatment, irrespective of line of therapy.
6. Must have moderate or severe hepatic impairment (as defined by the NCI organ dysfunction working group (NCI-ODWG) criteria.
Note: Patients with mild hepatic dysfunction (total bilirubin >1 to 1.5 × ULN OR AST > ULN) may be included if liver function tests are stable for the past 3 months and enrollment is approved in writing by the Sponsor’s Medical Monitor.
a) Moderate Hepatic dysfunction arm: ≥1 week of documented moderate hepatic impairment (total bilirubin>1.5–3 × ULN, any level of AST).
b) Severe Hepatic dysfunction arm: ≥1 week of documented severe hepatic impairment (total bilirubin >3–10 × ULN, any level of AST).
For Combination Therapy Part only:
7.Previous treatment lines (adjuvant or neoadjuvant therapy is not counted as one line of systemic
therapy):
a) Arm A: For patients with NSCLC, have received 1-2 prior line(s) of systemic
anti-cancer treatment with 1 regimen including an anti-PD-1/L1 mAb.
b) Arm C: For patients with CRC participating in the combination arm with
FOLFIRI, 1-2 prior lines of systemic therapy are allowed. Patient with CRC is not a candidate for curative resection of metastatic lesions.
8. Must have hepatic function as follows:
a) Arm A (combination with docetaxel): Patients with NSCLC who are to receive docetaxel and have bilirubin ≤ ULN, and AST and/or ALT ≤ 1.5 x ULN.
b) Arm C: total bilirubin ≤ 1.5 × ULN and AST ≤ 2.5 x ULN, AST ≤ 2.5 x ULN.
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| E.4 | Principal exclusion criteria |
Common exclusion criteria for all patients:
1. Have inadequate hematopoietic function defined as (without transfusion or growth factor
support within 7 days prior to first dose):
a. absolute neutrophil count (ANC) <1.5 × 109/L; platelet count (PLT) <100 × 109/L; or hemoglobin (Hb) <9 g/dL. (Note: This does not apply to the
MHI and SHI arms.)
2. Have inadequate renal function defined as a calculated creatinine clearance (CrCl) of <20 mL/min using the formula of Cockcroft and Gault.
3. Have any other medical condition especially any gastrointestinal (GI) dysfunctions or GI disease that could interfere with the absorption of selinexor (e.g., inability to swallow or retain oral medications, malabsorption syndrome, a history of GI surgery which may result in intestinal blind loop, significant gastroparesis, unresolved nausea, vomiting, or diarrhea [National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) Grade >1]).
4. Ongoing infection requiring parenteral antibiotics, antivirals, or antifungals on Day 1 dosing.
5. Prior exposure to a SINE compound or selinexor.
6. Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:
a. Not recovered from major surgery ≤21 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted.
b. Have ongoing clinically significant anti-cancer therapy-related toxicities CTCAE Grade >1. Patients with any of the following will not be excluded: immune checkpoint-related endocrinopathies that are well controlled with hormonal supplements, patients with electrolyte abnormalities that are well-managed with supplementation, patients with Grade 2 lymphopenia, or patients with alopecia of any grade. In specific cases, patients whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor’s Medical Monitor.
Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing.
d. Radiotherapy within 4 weeks before the study. Palliative radiotherapy >14 days prior to the study is allowed.
e. Received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug (whichever is shorter), prior to C1D1.
7. Serious active psychiatric or active medical condition that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous.
8. In the opinion of the Investigator, patients who are below their ideal body weight and would be unduly impacted by changes in their weight.
9. Known allergy to selinexor (all patients), docetaxel (NSCLC Arm A only), OR 5-FU, leucovorin, or irinotecan (CRC Arm C only).
10. Female patients who are pregnant or breastfeeding.
For Monotherapy Part only:
11. Have ECOG performance status ≥4 for patients to be enrolled into the MHI and SHI arms of the study.
12. For MHI and SHI arms: ANC <1 × 109/L; PLT <75 × 109/L; or Hb <8 g/dL.
13. Received strong cytochrome P450 3A (CYP3A) inhibitors ≤7 days prior to Day 1 dosing OR strong CYP3A inducers ≤14 days prior to Day 1 dosing.
14. Inability or unwillingness to undergo a series of PK sampling.
For Combination Therapy Part only:
15. Have ECOG performance status of ≥3 for Arms A and ECOG ≥2 for Arm C.
16. Arm C: Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Monotherapy Part
The following plasma PK parameters for selinexor for the 2 formulations and different
hepatic function:
•area under the concentration-time curve (AUC) from time 0 to time of last concentration measured (AUC0–t) and from time 0 extrapolated to infinity (AUC0–inf)
•maximum plasma concentration (Cmax)
Combination Therapy Part: Arm A
•ORR per RECIST 1.1
Combination Therapy Part: Arm C
•Based on, physical examination results, clinical laboratory results by means of the occurrence,
nature and severity of AEs
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to the end of trial |
|
| E.5.2 | Secondary end point(s) |
Monotherapy Part
The following PK parameters for selinexor for the 2 formulations in plasma:
•time to maximum observed concentration (Tmax)
•terminal elimination rate constant (λz)
•terminal half-life (t1/2)
•apparent clearance (CL/F)
•apparent volume of distribution (Vd/F)
The following PK parameters for selinexor in plasma:
•fraction unbound (fu)
•maximum free-drug concentration (Cmaxu)
•area under the free-drug concentration-time curve from time zero extrapolated to infinity (AUCu)
•apparent free-drug clearance (CLu/F)
•apparent free-drug volume of distribution (Vu/F)
•Based on AE reports, physical examination results (including vital signs), and clinical
laboratory results by means of the occurrence, nature and severity of AEs
Combination Therapy Part: Arm A
•PFS, DOR, DCR, and OS per RECIST 1.1
•Based on AE reports, physical examination results (including vital signs), and clinical laboratory results by means of the occurrence, nature and severity of AEs
Combination Therapy Part: Arm C
•ORR, DCR, DOR, PFS, and OS per RECIST 1.1
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline to the end of trial |
|
| 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 | Yes |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | No |
| 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 | Yes |
| 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 |
|
| 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
|
| Response and survival follow-up every 3 months up to 1 year, after the 30-day Safety Visit (Last Visit) of the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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 |
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