ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors

Objectives:

Primary Objectives:

Determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of
ALRN-6924 in combination with paclitaxel in adult patients with advanced or metastatic solid
tumors with wild-type (WT) TP53.

Evaluate the safety and tolerability of ALRN-6924 in combination with paclitaxel in patients
with advanced or metastatic WT TP53 solid tumors.

Key Secondary Objective:

Evaluate the anti-tumor activity of ALRN-6924 in combination with paclitaxel in solid tumors
(in dose escalation) and hormone-receptor positive breast cancer (in expansion).

Other Secondary Objectives:

Describe the pharmacokinetics (PK) of ALRN-6924 and paclitaxel in plasma following single and
multiple intravenous (IV) infusions (Cycle 1 Day 1, D2, D15 and Cycle 2 D1).

Inclusion Criteria:

1. 18 years of age or older

2. Histologically- or cytologically-confirmed solid tumors (excluding lymphomas) that are
metastatic or unresectable and that meet the following criteria: a) Escalation and
expansion cohorts: wild type (WT) TP53 status defined as no mutation on a Clinical
Laboratory Improvement Amendments (CLIA)-certified next-generation sequencing (NGS)
assay that has sequenced the full length TP53 gene. Patients can be enrolled based on
tissue testing or liquid biopsies. If enrolled based on liquid biopsies, testing
should have detected other somatic mutations;

3. (CONT) b) Expansion cohort only: estrogen receptor (ER) positive (> 1%), human
epidermal growth factor 2 (HER2) negative, WT TP53 metastatic or inoperable locally
advanced or locally recurrent breast cancer, regardless of progesterone receptor (PR)
status HER2 status will be defined according to the ASCO/CAP 2018 recommendation
(Patients can be HER2 0+ or 1+ by immunohistochemistry (IHC), 2+ by IHC and
fluorescent in situ hybridization (FISH) non-amplified to be considered HER2
negative).

4. Standard treatment with therapies known to confer a survival benefit does not exist,
is no longer effective or tolerated, or the patient declines standard treatment. For
the dose expansion cohort only, breast cancer patients with ER+, HER2- status must
have received prior endocrine therapy and CDK4/6 inhibitors.

5. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. In
the dose escalation stage, patients without measurable disease by RECIST 1.1, but
evaluable disease are also eligible.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

7. Demonstrate adequate organ function as defined by the parameters listed below: a)
Serum creatinine /= 45 mL/min/1.73m2 by
CKD-EPI equation for subjects with creatinine levels > 1.5 x institutional ULN; b)
Total bilirubin bilirubin levels > 1.5 x ULN, or unless due to Gilbert's Syndrome; c) Alanine
aminotransferase (ALT)/ aspartate aminotransferase (AST) if hepatic abnormalities are related to underlying liver metastases or liver/biliary
primary; d) Absolute neutrophil count (ANC) >/=1500/mm3(without GCSF in the 2 weeks
prior to treatment start); e)Platelet count >/= 100,000/mm3; f) Hemoglobin >/= 9 g/dL
(without blood transfusion in the 2 weeks prior to treatment start); g) International
normalized ratio (INR) and activated partial thromboplastin time (aPTT)
8. All patients (males and females) of childbearing potential must agree to use medically
effective contraception during the study and for 6 months after the last dose of study
drugs. Females must have a negative serum pregnancy test during screening and a
negative urine pregnancy test at study day 1 prior to initiation of treatment.

9. Have no concomitant medical condition (including, but not limited to, ongoing or
active infection or any psychiatric disorder), that in the judgment of the
investigator will interfere with the patient's ability to participate in the study or
render such participation medically inappropriate.

10. No medical history of another cancer (except basal or squamous cell skin cancer or in
situ cervical cancer, or carcinomas in situ or other malignancies with a >/=95% 5-year
survival) within 2 years of the start of study treatment.

11. No investigational drug or other anticancer treatments (including chemotherapy or
radiation therapy) within 21 days or at least 5 half-lives, whichever is shorter, of
the start of the study treatment.

12. No major surgery within 1 month of treatment and fully recovered.

13. Willing and able to provide informed consent.

Exclusion Criteria:

1. Previous treatment with investigational agents that inhibit MDM2 or MDMX activity.

2. Known active hepatitis B, hepatitis C and/or human immunodeficiency virus
(HIV)-positive patients who have a cluster of differentiation 4 (CD4) count < 200. No
antiretroviral medications that are CYP3A4 substrates will be allowed.

3. Requirement for therapeutic anticoagulation

4. Pre-existing history of or known cardiovascular risk: a) History of acute coronary
syndromes within 6 months prior to the first dose of ALRN-6924 (including myocardial
infarction, unstable angina, coronary artery bypass graft, angioplasty, or stenting);
b) Uncontrolled hypertension; c) Pre-existing cardiac failure (New York Heart
Association class III-IV); d) Atrial fibrillation on anti-coagulants; e) Clinically
significant uncontrolled arrhythmias; f) Corrected QTcF interval on screening
electrocardiography (ECG) >/=450 msec for males and >/=470 msec for females (QTcF >480
msec for any patient with a bundle branch block).

5. Clinically significant gastrointestinal bleeding within 6 months prior to the start of
study treatment.

6. Females who are pregnant or nursing.

7. Symptomatic central nervous system (CNS) metastases by history, clinical signs or
radiologic findings. Stable brain metastases (1 month after completion of treatment)
confirmed by imaging are allowed.

8. Known hypersensitivity to any study drug component.

9. The required use of any concomitant medications that are predominantly cleared by
hepatobiliary transporters, Organic-anion-transporting polypeptide (OATP) members
OATP1B1 and OATP1B3, on the day of the ALRN-6924 infusion or within 48 hours after an
ALRN-6924 infusion.

10. Patients with Grade >/=2 neuropathy will be excluded.