Phase 1b:Primary:- 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 extensive disease (ED) small cell lung cancer (SCLC) receiving…
ID
Source
Brief title
Condition
- Anaemias nonhaemolytic and marrow depression
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1b
Primary endpoint:
- Proportion of patients with National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) Grade 3/4 treatment
emergent adverse events (TEAEs)
Phase 2
Primary endpoint:
- Proportion of patients with Grade * 3 neutropenia in Cycle 1
Secondary outcome
Phase 1b:
Key secondary endpoint:
- Proportion of patients with Grade * 3 neutropenia in Cycle 1
Other secondary endpoints:
- 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
- Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1
- Progression free survival (PFS)
- Overall survival (OS)
- PK parameters (e.g., area-under-the-curve [AUC], maximum concentration
[Cmax], time of Cmax [tmax], half-life [t1/2]) of ALRN-6924
Phase 2:
Secondary endpoints:
- 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 febrile neutropenia
- Proportion of planned treatment cycles delayed due to toxicity
- Proportion of patients with NCI CTCAE Grade 3/4 TEAEs
- ORR
- PFS
- OS
- PK parameters (e.g., AUC, Cmax, tmax, t1/2) of ALRN-6924
Background summary
ALRN-6924 is a synthetic, cell-permeating, stapled peptide designed to disrupt
the interaction between the p53 tumor suppressor protein and its predominant
endogenous inhibitors, murine double minute X (MDMX) and murine double minute 2
(MDM2). ALRN-6924 is being developed by Aileron Therapeutics, Inc. (Aileron) as
a potential treatment for patients with advanced cancers with wild-type (WT)
TP53 tumor suppressor protein and for the supportive care of patients with
TP53-mutant tumors, but an intact p53 pathway in their non-malignant tissues.
The present protocol is designed to evaluate the myelopreservation effects of
ALRN-6924 when administered as supportive treatment during myelosuppressive
chemotherapy; specifically, during 2nd-line treatment with topotecan in
patients with TP53-mutated extensive disease (ED) small cell lung cancer
(SCLC).
Study objective
Phase 1b:
Primary:
- 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 extensive disease (ED) small cell lung cancer (SCLC) receiving
topotecan as 2nd-line treatment.
Secondary
- 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
Phase 2:
Primary
- 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
Secondary
- To further evaluate the safety and tolerability of ALRN-6924 as supportive
care during treatment with topotecan
- To further 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 further evaluate the PK profile of ALRN 6924 when administered with
topotecan
Study design
This is a Phase 1b/2, open-label, multicenter study of ALRN-6924 for the
prevention of topotecan-induced myelosuppression during 2nd-line treatment for
ED SCLC harboring TP53 mutations. During the Phase 1b portion of the study,
chemotherapy-induced myelosuppression in patients with TP53-mutated ED SCLC
undergoing 2nd-line treatment with topotecan. The Phase 1b part of the study
will consist of a dose optimization stage, a schedule optimization stage, and a
dose expansion stage. Two schedules of ALRN-6924 administration (either 24
hours or 6 hours prior to every topotecan infusion) will be evaluated. The RP2D
and recommended schedule of ALRN-6924 in combination with topotecan will be
determined in the Phase 1b dose optimization and schedule optimization stages
of the trial. This dose and schedule will be utilized in the Phase 1b dose
expansion and Phase 2 parts of the trial.
During the Phase 1b dose optimization stage, topotecan will be administered per
standard practice on Days 1-5 of 21-day cycles. Patients will be randomized to
receive 1 of 2 initial ALRN-6924 dose levels, to be administered on Days 0-4 of
each cycle, approximately 24 hours prior to each planned topotecan dose.
The severity of hematologic toxicities, particularly neutropenia,
thrombocytopenia, anemia and febrile neutropenia, will be determined and
compared to the severity of these toxicities when topotecan is administered
alone, based on historical controls.
If pre-determined criteria for safety and myelopreservation are met, an
additional 8 patients at each of these two dose levels will be evaluated, for a
total of 14 patients at each of the two dose levels. If pre-determined
criteria for safety and myelopreservation are not met, up to 6 additional
(nonrandomized) dose levels may be evaluated. The safety and tolerability of
each ALRN-6924 dose level will be assessed during Phase 1b and a Data Review
Committee (DRC) will assess these data and the hematologic toxicity data at the
end of Phase 1b, in order to select a recommended Phase 2 dose. This committee
will also review safety data on a regular basis and will review each ALRN-6924
dose level after 6 patients enrolled to that dose level have completed one full
cycle of ALRN-6924 supportive therapy, in order to assess the safety and
tolerability of that dose level, before additional patients are enrolled.
If pre-determined criteria for safety and myelopreservation activity are met
and the DRC identifies an RP2D, the Phase 2 portion of the study will be
triggered.
RP2D. During the Phase 1b schedule optimization stage of the study, topotecan
will be administered as described for the dose optimization stage. Patients
will receive 1 of 2 dose levels of ALRN-6924, to be administered on Days 1-5 of
each cycle, approximately 6 hours prior to each planned topotecan dose. The 2
dose levels ALRN-6924 to be evaluated with this alternative schedule will be
determined based on results from the Phase 1b dose optimization stage.
Following completion of the Phase 1b schedule optimization evaluation, a
recommended schedule for ALRN-6924 (either 24 hours or 6 hours prior to every
topotecan infusion) will be determined.
Following identification of the recommended dose and schedule of ALRN-6924, the
DRC will make a recommendation regarding initiation of the Phase 1b expansion
and/or the Phase 2 portion of the study. Based on the DRC recommendation, the
Sponsor will determine which of these cohorts to open first. It is possible
that not all study sites will participate in the Phase 1b dose expansion cohort.
In the randomized Phase 1b expansion stage, 20 patients with ED SCLC harboring
p53 loss of function mutations and requiring 2nd-line treatment with topotecan
will be randomized in a 1:1 ratio to receive:
- Treatment with topotecan + ALRN-6924 per RP2D and recommended schedule during
Cycle 1; and topotecan alone during Cycle 2.
- Treatment with topotecan alone during Cycle 1; and topotecan + ALRN-6924
during Cycle 2 per RP2D and recommended schedule.
In all subsequent treatment cycles(Cycles *3), all patients will receive
treatment with topotecan + ALRN-6924.
In Phase 2, patients with ED SCLC harboring p53 loss of function mutations
requiring 2nd-line treatment with topotecan will be randomized 1:1 to either
receive topotecan alone or topotecan with supportive ALRN-6924 treatment.
Monitoring of hematologic toxicities will proceed as in Phase 1b.
Intervention
All patients will be treated with Topotecan and a dose of ALRN 6924
During the Phase 1b portion of the study,topotecan will be administered per
standard practice on Days 1-5 of 21-day cycles.Patients will be randomized to
receive 1 of 2 initial ALRN-6924 dose levels, to be administered on Days 0-4 of
each cycle, approximately 24 hours prior to each
planned topotecan dose.
During the Phase 1b schedule optimization stage of the study, topotecan will be
administered per standard practice on Days 1-5 of 21-day cycles. ALRN-6924 will
be administered at 1 of 2 dose levels on Days 1-5 of each cycle approximately 6
hours prior to each planned topotecan dose. The 2 dose levels of ALRN-6924 to
be evaluated with this alternative schedule will be determined based on results
from the dose optimization stage of the Phase 1b trial. Patients will be
enrolled at Dose Level 1 initially followed by enrolment in Dose Level 2. Six
patients will initially be enrolled at each dose level; if pre-determined
criteria for safety and myelopreservation are met, an additional 8 patients at
each of these 2 dose levels will be evaluated, for a total of 14 patients at
each of the 2 dose levels. Following completion of the Phase 2 portion of the
study will be triggered. In Phase 2, 1b schedule optimization evaluation, a
recommended schedule for ALRN-6924 (either 24 hours or 6 hours prior to every
topotecan infusion) will be determined.
During Phase 2, patients randomly assigned to the experimental arm will receive
ALRN-6924 as an IV infusion over 1 hour at the RP2D on Days 0-4 of every 21-day
cycle and topotecan at a dose of 1.5 mg/m2 on Days 1-5 of each cycle. Patients
randomly assigned to the control arm will receive topotecan per the same dose
and schedule but will not receive any administrations of ALRN-6924.
Study burden and risks
The patients will be treated with Topotecan and ALRN-6924 for a maximum of 6
cycles the total duration for phase Ib will be 5 months. During each cycle the
patient will visit the hospital 6-7 times. With the maximum nr of cycles 44
visits are performed.
- Possible side effects of the treatment.
- Possible adverse effects/discomforts of the evaluations in the study e.g.
venapuction or CT scans.
- Incidental findings: participation in the study may lead to additional
findings about your health eg. HIV HBV HCV.
Arsenal Way 490
Watertown MA 02472
US
Arsenal Way 490
Watertown MA 02472
US
Listed location countries
Age
Inclusion criteria
Inclusion Criteria:
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.
Exclusion criteria
Exclusion Criteria:
1. Known hypersensitivity to any component of study treatment including
mannitol, which is an excipient in topotecan.
2. More than one line of prior chemotherapy for ED SCLC (prior immunotherapy is
permitted, concurrent with or subsequent to firstline chemotherapy).
Previous treatment with platinum-based chemotherapy concomitant with
radiotherapy for limited disease is allowed if completed at least 6 months
prior to enrolment into the current trial.
3. Presence of active 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.
4. 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/*L.
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
5. Clinically significant electrolyte abnormalities
6. Clinically unstable cardiac disease, including unstable atrial fibrillation,
symptomatic bradycardia, unstable congestive heart failure, active myocardial
ischemia, or indwelling temporary pacemaker
7. 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.
8. Pregnant or lactating women
9. Hereditary angioedema of any severity or severe or life-threatening
angioedema due to any cause.
10. Major surgery (e.G. opening up a mesenchymal barrier) within 28 days of
enrolment. Please consult Medical monitor as needed
11. Significant weight loss (*15% body weight) within the 4 weeks prior to
enrolment.
12. Treatment with an investigational agent for any indication within the
shorter of 14 days or 5 half-lives, if the half-life is known
13. The required use of any concomitant medications that are predominantly
cleared by hepatobiliary transporters, organic anion transporter polypeptide
[OATP] members OATP1B1 and OATP1B3 on the day of the first ALRN-6924 infusion
to within 48 hours after the last ALRN-6924 infusion in a treatment cycle (see
Appendix A)
14. Other medications, severe acute/chronic medical or psychiatric condition,
or laboratory abnormality that may increase the risk associated with study
participation or study drug administration, or may interfere with the
interpretation of study results, and in the judgment of the investigator would
make the patient inappropriate for entry into this study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-001848-21-NL |
| ClinicalTrials.gov | NCT04022876 |
| CCMO | NL70430.031.19 |