| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Small Cell Lung Cancer and Non small cell lung cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung 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 |
SCLC, phase 1b
To evaluate the safety and tolerability and determine the recommended Phase 2 dose (RP2D) and schedule of ALRN-6924 when administered to patients with TP53-mutated ED SCLC receiving topotecan as 2nd line treatment
SCLC, phase 2
To evaluate the myelopreservation effects of ALRN-6924 when administered at the RP2D and schedule to patients with TP53-mutated ED SCLC undergoing 2nd line treatment with topotecan
NSCLC
To evaluate the preliminary myelopreservation effects of ALRN-6924 when administered to patients with TP53-mutated advanced NSCLC of adenocarcinoma histology receiving 1st_line treatment with carboplatin plus pemetrexed with or without immunotherapy
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| E.2.2 | Secondary objectives of the trial |
SCLC
• To evaluate the preliminary myelopreservation effects of ALRN-6924 when administered to patients with TP53-mutated ED SCLC undergoing 2nd line treatment with topotecan
• To evaluate the efficacy of topotecan when administered as 2nd-line treatment for patients with TP53-mutated ED SCLC who are receiving supportive treatment with ALRN-6924
• To evaluate the pharmacokinetic (PK) profile of ALRN 6924 when administered with topotecan
NSCLC
• To evaluate the safety and tolerability of ALRN-6924 when administered to patients with TP53-mutated advanced NSCLC of adenocarcinoma histology receiving 1st line treatment with carboplatin plus pemetrexed with or without immunotherapy.
• To evaluate the efficacy of 1st_line treatment with carboplatin plus pemetrexed with or without immunotherapy in patients with TP53-mutated advanced NSCLC of adenocarcinoma histology who are receiving supportive treatment with ALRN-6924
• To assess concentrations of ALRN-6924 in blood during treatment. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
SCLC
1. Males and females age 18 years or older.
2. Ability to understand the requirements of this clinical trial and willingness to provide written informed consent
3. Histopathological confirmation of ED SCLC that has recurred or been refractory to one line of treatment with standard platinum-based chemotherapy or immuno-chemotherapy. Patients who received immunotherapy after platinum-based chemotherapy remain eligible.
4. Mutated TP53: no wild type (WT) TP 53 gene copies within the tumor (i.e., biallelic mutation, biallelic deletion, or mutation/deletion), as assessed by next generation sequencing (NGS)
5. Measurable disease using RECIST 1.1
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
7. Adequate hematological status:
a. absolute neutrophil count (ANC) ≥1500/L
b. platelet count ≥100,000/L
c. hemoglobin ≥9.0 g/dL
8. Adequate hepatic and renal function:
a. total bilirubin ≤1.5 X upper limit of normal (ULN) or ≤ 3 X ULN in the presence of Gilbert syndrome or liver metastases
b. alkaline phosphatase (ALP), aspartate aminotransferase (AST [SGOT]), and alanine aminotransferase (ALT [SGPT]) ≤ 2.5 X ULN in the absence of liver metastases
c. ALP, AST (SGOT), and ALT (SGPT) ≤5 X ULN in the presence of liver metastases
d. serum creatinine <1.5 X ULN or calculated creatinine clearance ≥ 40 mL/min (C&G or EDTA)
9. Recovery from the acute toxic effects of all prior therapies to Grade ≤1
10. The shorter of 5 half-lives or 4 weeks must have elapsed since any prior systemic therapy, unless no drug-drug interactions with study treatment would be anticipated and the patient had unequivocal radiologic disease progression during the prior line of therapy.
11. Males and female patients of child-bearing potential must agree to use an acceptable method of birth control for the duration of study treatment and for 3 months (male patients with female partner of child-bearing potential) or 6 months (female patients of child-bearing potential) following the last dose of study treatment.
NSCL
1. Males and females age 18 years or older.
2. Ability to understand the requirements of this clinical trial and willingness to provide written informed consent.
3. Histopathological confirmation of Stage IV NSCLC of adenocarcinoma histology. Cytological diagnosis of NSCLC is acceptable if sufficient tumor tissue is available for p53 mutation analysis. Liquid biopsies are also acceptable.
4. Presence of p53 mutation(s) in tumor tissue or circulating cell free DNA as assessed by next generation sequencing (NGS).
5. Patients who are deemed to be good candidates for chemotherapy with carboplatin and pemetrexed, OR standard immunochemotherapy that includes carboplatin and pemetrexed, with a planned delivery of at least 4 chemotherapy treatment cycles. Concurrent use of bevacizumab as per local treatment practice, is permitted.
6. No prior systemic therapy for any stage NSCLC, including chemotherapy, immunotherapy or targeted drugs (e.g., inhibitors of EGFR, ALK, ROS, RET, HER2, BRAF etc.).
7. Absence of tumor genomic aberrations of EGFR, ALK or other actionable genomic aberrations, as per local standard of care.
8. Measurable disease using RECIST 1.1
9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
10. Adequate hematological status without supportive care measures during screening period:
a. ANC ≥1500/mL
b. platelet count ≥100,000/mL
hemoglobin ≥9.0 g/dL
11. Adequate hepatic and renal function:
a. total bilirubin ≤1.5 X upper limit of normal (ULN) or ≤ 3 X ULN in the presence of Gilbert syndrome or liver metastases
b. alkaline phosphatase (ALP), aspartate aminotransferase (AST [SGOT]), and alanine aminotransferase (ALT [SGPT]) ≤ 2.5 X ULN in the absence of liver metastases
c. ALP, AST (SGOT), and ALT (SGPT) ≤5 X ULN in the presence of liver metastases
d. serum creatinine <1.5 X ULN or calculated creatinine clearance ≥ 45 mL/min (C&G or EDTA)
12. Males and female patients of child-bearing potential must agree to use an acceptable method of birth control for the duration of study treatment and for 3 months (male patients with female partner of child-bearing potential) or 6 months (female patients of child-bearing potential) following the last dose of study treatment. |
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| E.4 | Principal exclusion criteria |
SCLC
1.Known hypersensitivity to any component of study treatment.
2. Presence of active and symptomatic central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable, with no evidence of radiographic or neurologic progression during the screening period and no requirement for steroids for at least 15 days before enrolment.
3. Advanced NSCLC tumors with EGFR mutations or ALK re-arrangement or other actionable genetic aberrations for which an approved targeted treatment is available. Patients who received prior treatment with EGFR or ALK inhibitors or other systemic drugs or immunotherapy for NSCLC are not eligible for participation.
4. Patients who are candidates for anti-PD-1 monotherapy in 1stline advanced NSCLC (e.g., tumors with high PD-L1 expression).
5. Patients who received prior systemic treatment for earlier stage NSCLC disease other than surgery, immunotherapy and/or localized radiotherapy. Patients who received neoadjuvant or adjuvant chemotherapy, or radiochemotherapy are not eligible for participation.
6. Uncontrolled intercurrent illness including but not limited to:
a. Clinically significant, active, uncontrolled infection including human immunodeficiency virus (HIV), or hepatitis B or C
i. Patients with HIV must be on effective antiretroviral therapy for ≥ 4 weeks prior to enrollment and have HIV viral load < 400 copies/mL, have had no acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the past 12 months, and have CD4+ count ≥ 350 cells/µL.
ii. Patients with chronic hepatitis B virus (HBV) must be on antiviral therapy and have HBV viral load below the limits of detection.
iii. Patients with hepatitis C virus (HCV) must be on or have completed antiviral therapy and have an HCV viral load below the limits of detection.
b. Uncontrolled hypertension
c. Uncontrolled diabetes mellitus
7. Serum albumin <30 g/L
8. Clinically significant electrolyte abnormalities
9. Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker
10. History of prior malignancy; patients with a known malignancy that does not affect overall well-being and ability to participate in the study can be considered in consultation with the Medical Monitor. see more exclusion criteria in the protocol
NSCL
Exclusion Criteria:
1. Known hypersensitivity to any component of study treatment.
2. Presence of active and symptomatic central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable, with no evidence of radiographic or neurologic progression during the screening period and no requirement for steroids for at least 15 days before enrolment.
3. Advanced NSCLC tumors with EGFR mutations or ALK re-arrangement or other actionable genetic aberrations for which an approved targeted treatment is available. Patients who received prior treatment with EGFR or ALK inhibitors or other systemic drugs or immunotherapy for NSCLC are not eligible for participation.
4. Patients who are candidates for anti-PD-1 monotherapy in 1st-line advanced NSCLC (e.g., tumors with high PD-L1 expression).
5. Patients who received prior systemic treatment for earlier stage NSCLC disease other than surgery, immunotherapy and/or localized radiotherapy. Patients who received neoadjuvant or adjuvant chemotherapy, or radiochemotherapy are not eligible for participation.
6. Patients who require growth factor or transfusion support of hematologic function during the screening period. Rescreening is not permitted for patients who do not meet criteria for adequate hematologic status. see more in the protocol
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| E.5 End points |
| E.5.1 | Primary end point(s) |
SCLC, phase 1b
Proportion of patients with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 3/4 treatment emergent adverse events (TEAEs)
SCLC, phase 2
Proportion of patients with Grade ≥ 3 neutropenia in Cycle 1
NSCL
Proportion of completed treatment cycles (without chemotherapy dose reductions or delays and without the use of growth factors or transfusions) that are free of:
1. Grade 3/4 neutropenia
2. Grade 3/4 thrombocytopenia
3. Grade 3/4 anemia
4. Grade 4 neutropenia
Febrile neutropenia
Other Primary Endpoints
1. Duration of Grade 4 neutropenia events
2. Duration of Grade 3/4 neutropenia at first occurrence
3. Proportion of completed treatment cycles without chemotherapy dose reduction or without the use of growth factors or transfusions
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
SCLC, phase 1b: Dose Limiting Toxicity
SCLC, phase 2: Cycle 1
NSCLC
At least 4 treatment cycles with chemotherapy or immunochemotherapy and ALRN-6924 or placebo.
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| E.5.2 | Secondary end point(s) |
SCLC, phase 1b
• Proportion of patients with Grade ≥ 3 neutropenia in Cycle 1
SCLC, phase 2
• Proportion of patients with Grade ≥ 3 neutropenia in Cycle 2 and beyond
• Time to first incidence of Grade ≥ 3 neutropenia
• Duration of Grade ≥ 3 neutropenia
• Proportion of patients with Grade ≥ 3 thrombocytopenia
• Proportion of patients with Grade ≥ 3 anemia
• Proportion of patients with febrile neutropenia
• Proportion of planned treatment cycles delayed due to toxicity
• Proportion of patients with NCI CTCAE Grade 3/4 TEAEs
• ORR by RECIST 1.1
• PFS
• OS
• PK parameters (e.g., AUC, Cmax, tmax, t1/2) of ALRN-6924
NSCLC
• Proportion of patients with NCI CTCAE Grade 3/4 TEAEs
• ORR by RECIST 1.1
• PFS
• Concentrations of ALRN-6924 in blood on Days 0, 1, and 2 during Cycle 1 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SCLC, phase 1b: Cycle 1
SCLC, phase 2: Cycle 2 and beyond
NSCLC
Full analysis Set: all enrolled patients who received at least one dose of ALRN-6924 or placebo and initiated chemotherapy or immunotherapy treatment
Per Protocol Population: All patients who meet eligibility criteria, have received the assigned study drug treatment and have completed at least 4 treatment cycles with chemotherapy or immunochemotherapy and ALRN-6924 or placebo. Patients who do not complete at least 4 treatment cycles due to treatment-related toxicities are evaluable and will be included in the analysis. Patients who do not complete at least 4 treatment cycles due to disease progression or any reason other than treatment-related toxicity will not be included in the analysis.
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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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| 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 |
| NSLC cohort is double blinded and placebo controlled the SCLC cohort is open label |
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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 | Yes |
| E.8.2.3.1 | Comparator description |
| Topotecan for SCLC, pemetrexed plus carboplatin plus placebo for NSCL cohort |
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| 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
| 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 | 12 |
| 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 |
| United States |
| Poland |
| Netherlands |
| Spain |
| Bosnia and Herzegovina |
| Croatia |
| Serbia |
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| 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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| Patients will be followed for overall survival until death, or study completion or termination by the Sponsor. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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