ALRN-6924 in Patients With Advanced Solid Tumors or Lymphomas

Study Overview
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Brief Summary
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This study evaluates the anti-tumor effects of ALRN-6924 in patients with advanced solid tumors or lymphomas with WT TP53.

Detailed Description
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Open label, multi center, Phase 1 (dose escalation) and Phase 2a (dose expansion) study design to evaluate safety, tolerability, PK, PD and anti-tumor effects of ALRN-6924, alone or in combination with palbociclib, in patients with advanced solid tumors or lymphomas with wild-type (WT) TP53. ALRN-6924 is a stabilized cell-permeating peptide designed to disrupt the interaction between the p53 tumor suppressor protein and its predominant endogenous inhibitors, murine double minute 2 (MDM2) and murine double minute X (MDMX). The Phase 1 portion of the study will enroll adults with histologically or cytologically confirmed malignancies that are metastatic or unresectable and for which standard treatment(s) are not available or are no longer effective. The Phase 2a portion of the study consists of separate cohorts that will enroll distinct groups of patients with specific solid tumors and/or lymphomas to further investigate the clinical safety profile and potential efficacy of ALRN-6924 alone or in a combination regimen. Treatment will continue until unacceptable toxicity, patient or physician decision to discontinue therapy or disease progression that is either symptomatic, rapidly progressive, requires urgent intervention or is associated with a decline in performance status. Patients with PTCL have been selected as a group to be further studied in Phase 2a. Patients with MDM2-amplified or MDM2/CDK4-co-amplified solid tumors have been selected as another group to be further studied in Phase 2a.

Official Title
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A Phase 1/2a Open-Label Study to Determine the Safety and Tolerability of ALRN-6924 Alone or in Combination in Patients With Advanced Solid Tumors or Lymphomas Expressing Wild-Type p53 Protein

Conditions
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Solid Tumor, Lymphoma, Peripheral T-Cell Lymphoma

Intervention / Treatment
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* Drug: ALRN-6924


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically or cytologically confirmed solid tumor or lymphoma that is not amenable to standard therapies. Cohort specific biomarkers, including confirmed or anticipated WT TP53 (Phase 1 and PTCL expansion cohorts) and MDM2-amplification or MDM2/CDK4-co-amplification (solid tumor expansion cohort) At least one target lesion that is measurable by RECIST 1.1, RANO or IWG 2014, as appropriate for tumor type ECOG (Eastern Cooperative Oncology Group) performance status 0-1 Adequate coagulation and hematologic function Adequate hepatic and renal function Sufficient wash out from prior therapies and recovery from all significant acute toxicities Key Exclusion Criteria Prior treatment with an MDM2 inhibitor, with protocol specified exceptions Known hypersensitivity to any study drug component Protocol specified cardiovascular risk factors Clinically significant gastrointestinal bleeding within 6 months Clinically significant third-space fluid accumulation Active uncontrolled infection, including HIV/AIDS or Hepatitis B or C HPV positive tumors Second malignancy within two years, with protocol specified exceptions Pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Regimen A (DR-A)<br>Drug: ALRN-6924 Weight-based-dosing administered IV on days 1, 8 and 15 of a 28-day cycle. | Drug: ALRN-6924<br>* ALRN-6924 will be administered as an IV infusion<br>|
| Experimental: Dose Regimen B (DR-B)<br>Drug: ALRN-6924 Weight-based-dosing administered IV on days 1, 4, 8 and 11 of a 21-day cycle | Drug: ALRN-6924<br>* ALRN-6924 will be administered as an IV infusion<br>|
| Experimental: Dose Regimen C (DR-C)<br>Drug: ALRN-6924 Weight-based-dosing administered IV on days 1, 3 and 5 of a 21-day cycle | Drug: ALRN-6924<br>* ALRN-6924 will be administered as an IV infusion<br>|
| Experimental: Combination with palbociclib<br>Drug: ALRN-6924 Weight-based-dosing administered IV on days 1, 8 and 15 of a 28-day cycle Drug: Palbociclib Fixed-dose capsule administered orally on days 1 through 21 of a 28-day cycle | Drug: ALRN-6924<br>* ALRN-6924 will be administered as an IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of ALRN-6924 in adult patients with advanced solid tumors or lymphomas with wild-type (WT) TP53 who are refractory to or intolerant of standard therapy, or for whom no standard therapy exists - Phase 1 | Number of participants with treatment-related adverse events as assessed by CTCAE v.4.0 | From Day 1 of treatment until 30 days after the last cycle of treatment (each cycle is 28 days) | 
| Evaluate the safety and tolerability of ALRN-6924 in adult patients with advanced solid tumors or lymphomas with wild-type (WT) TP53 who are refractory to or intolerant of standard therapy, or for whom no standard therapy exists - Phase 2 | Number of participants with treatment-related adverse events as assessed by CTCAE v.4.0 | From Day 1 of treatment until 30 days after the last cycle of treatment (each cycle is 28 days) | 
| Determine the maximum tolerated dose (MTD) - Phase 1 | Determine the dose limiting toxicities (DLT) and the maximum tolerated dose (MTD) or the optimal biological dose (OBD) of ALRN-6924 in adult patients with advanced solid tumors or lymphomas | From the first dose until the end of the first cycle (each cycle is 28 days) | 
| Determine Overall Response Rate - Phase 2 | The proportion of efficacy-evaluable patients who achieve complete response (CR) or partial response (PR), per investigator assessment, in accordance with RECIST 1.1 or iRECIST (for solid tumor patients) or Response Assessment in Neuro-Oncology (RANO) criteria (for glioblastoma patients). | From the first dose until the first documented date of progression or date of death from any cause, whichever comes first, assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Pharmacokinetic parameters of ALRN-6924 when administered to patients with advanced solid tumors or lymphomas | Peak Plasma Concentration (Cmax) | 8 weeks | 
| Determine Pharmacokinetic parameters of ALRN-6924 when administered to patients with advanced solid tumors or lymphomas | Area under the plasma concentration versus time curve (AUC) | 8 weeks | 
| Determine Pharmacokinetic parameters of ALRN-6924 when administered to patients with advanced solid tumors or lymphomas | Time of Peak Plasma Concentration (Tmax) | 8 weeks | 
| Assess additional measures of anti-tumor activity, including duration of response, progression free survival, overall survival and time to response | The proportion of efficacy-evaluable patients who achieve complete response (CR) or partial response (PR), per investigator assessment, in accordance with RECIST 1.1 or iRECIST (for solid tumor patients) or Response Assessment in Neuro-Oncology (RANO) criteria (for glioblastoma patients). | From the first dose until the first documented date of progression or date of death from any cause, whichever comes first, assessed up to 100 months | 
| Assess additional pharmacologic properties, including biomarkers and immunogenicity | The correlation of response with MDM2, MDMX, and/or CDK4 gene copy number and other genetic and protein biomarkers | Up to 24 weeks |