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
Phase: PHASE1
Conditions: Solid Tumor, Lymphoma, Peripheral T-Cell Lymphoma
Sponsor: Aileron Therapeutics, Inc.



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INVESTIGATOR’S SIGNATURE PAGE 
 
Protocol Number 
ALRN-6924-1-01 
 
Protocol Title 
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 
 
Protocol Amendment 7 – 25 September 2018 
 
I have reviewed this protocol and agree that it contains all the information necessary to conduct the study 
as required.  I am aware of my responsibilities as an Investigator under the guidelines of the International 
Council on Harmonization (ICH) Good Clinical Practice (GCP), the Declaration of Helsinki, and the 
Code of Federal Regulations (CFR) Title 21.  I will conduct the trial in accordance with the principles of 
ICH GCP, the Declaration of Helsinki and the CFR. 
I will maintain as confidential all written and verbal information provided to me by the Sponsor, 
including but not limited to, the protocol, case report forms, Investigator’s Brochure, material supplied at 
Investigator meetings, minutes of teleconferences, etc.  Such material will only be provided as necessary 
to site personnel involved in the conduct of the trial, involved IRBs or local regulatory authorities. 
I will obtain written informed consent from each prospective trial patient or each prospective trial 
patient’s legal representative prior to conducting any protocol-specified procedures.  The ICF used will 
have the approval of the IRB appropriate for each institution. 
I will maintain adequate source documents and record all observations, treatments and procedures 
pertinent to trial patients in their medical records.  I will accurately complete the case report forms 
supplied by the Sponsor in a timely manner.  I will ensure that my facilities and records will be available 
for inspection by representatives of the Sponsor, the IRB, or relevant regulatory authorities.  I will ensure 
that my staff and I are available to meet with Sponsor representatives during regularly scheduled 
monitoring visits. 
I will notify the Sponsor or its designee within 24 hours of any serious adverse events.  Following this 
notification, a written report describing the serious adverse event will be provided to the Sponsor or its 
designee as soon as possible, but no later than four working days following the initial notification. 
 
 
 
 
 
 
 
 
 
Investigator’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
INVESTIGATOR’S SIGNATURE 
 
 
 
 
 
DATE 

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ALRN-6924-1-01 SYNOPSIS 
 
Protocol Number 
ALRN-6924-1-01 
Protocol Title 
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 
Name of Study Drug 
ALRN-6924 for IV infusion 
Sponsor 
Aileron Therapeutics, Inc. 
Phase of Development 
Phase 1/2a 
 
Research Facilities 
Multi Center 
Location 
USA 
Name of Active Ingredient 
ALRN-6924 
Study Drug Description 
ALRN-6924 is a Stapled Peptide clinical candidate 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).  ALRN-6924 drug product is a 
frozen or refrigerated liquid product supplied in single use glass vials 
in single dose strength of 75 mg in 5.0 mL, dissolved in 20 mM sodium 
phosphate, 240 mM trehalose, 300 ppm Polysorbate 20, and pH 7.5. 
Each vial contains recoverable 5.0 mL and is filled with formulated 
ALRN-6924 to 5.5 ± 0.2 mL. 
Palbociclib (IBRANCE®) 
Palbociclib is a cyclin-dependent kinase-4 and -6 inhibitor indicated for 
the treatment of hormone receptor (HR)-positive, human epidermal 
growth factor receptor 2 (HER2)-negative advanced or metastatic 
breast cancer in combination with an aromatase inhibitor as initial 
endocrine based therapy in postmenopausal women; or in combination 
with fulvestrant in women with disease progression following 
endocrine therapy. Palbociclib is available as 125 mg capsules, 100 mg 
capsules, or 75 mg capsules for oral use. 
Study Objectives – Phase 1 Dose Escalation (ALRN-6924 administered as single agent therapy) 
The primary objectives of the Phase 1 dose escalation are to: 
• 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 
• 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 
The secondary objectives of the Phase 1 dose escalation are to: 
• Describe the pharmacokinetics (PK) of ALRN-6924 and its metabolites in blood following single and multiple 
intravenous (IV) infusions 
• Assess potential patient biomarkers (e.g., p53 status, MDM2 and MDMX expression levels), the effect of 
ALRN-6924 treatment on these biomarkers, and possible correlation between these biomarkers and clinical response 
• Assess the effect of ALRN-6924 treatment on potential pharmacodynamic (PD) biomarkers in tumor biopsy 

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samples (including bone marrow aspirates) (e.g., p21, caspase, MDM2) and blood samples (e.g., macrophage 
inhibitory cytokine-1 [MIC-1]), and assess possible correlation between these biomarkers and clinical response   
• Evaluate potential clinical activity of ALRN-6924  
• Investigate the immunogenicity of ALRN-6924 
The exploratory objectives are to:  
• Starting at dose level 3: assess the effect of ALRN-6924 treatment on potential PD biomarkers (e.g., p21, p53, 
caspase) in circulating tumor cells (CTC), where detectable, or in mononuclear blood cells (MNC)  
• Assess the effects of ALRN-6924 treatment on cell-free DNA from blood 
Study Objectives – Phase 2a Dose Expansion in Peripheral T-cell Lymphoma (PTCL) (ALRN-6924 
administered as single agent therapy) 
The primary objectives of the Phase 2a dose expansion are to: 
• Assess overall response rate (ORR) 
• Further evaluate the safety and tolerability of ALRN-6924  
The secondary objectives of the Phase 2a dose expansion are to: 
• Describe the pharmacokinetics (PK) of ALRN-6924 and its metabolites in blood following single and multiple 
intravenous (IV) infusions in patient populations selected for dose expansion 
• Assess duration of response (DOR) 
• Assess progression free survival (PFS) 
• Assess overall survival (OS) 
• Assess PFS and OS at 1 year 
• Assess time to response 
• Assess the effect of ALRN-6924 treatment on potential pharmacodynamic (PD) biomarkers in tumor biopsy 
samples (including bone marrow aspirates, where clinically indicated) by measuring potential biomarkers such as 
e.g., p53, p21, caspase, MDM2, MDMX and in blood samples by measuring potential biomarkers such as MIC-1, 
and assessing possible correlation between these biomarkers and clinical outcomes   
• Investigate the immunogenicity of ALRN-6924 
The exploratory objectives of the Phase 2a dose expansion are to: 
• Assess the effects of ALRN-6924 treatment on cell-free DNA from blood and on potential PD biomarkers (e.g., 
p21, p53, caspase) in circulating tumor cells (CTC), where detectable, or in mononuclear blood cells (MNC) 
• Assess the effect of ALRN-6924 using alternative response criteria other than the IWG 2014 or RECIST 1.1 
criteria  

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Study Objectives – Phase 2a Dose Expansion in MDM2 amplified or MDM2/CDK4 co-amplified solid tumors 
(ALRN-6924 plus palbociclib) 
The primary objectives of this Phase 2a dose expansion cohort (added per Amendment 7) are to: 
• Assess ORR 
• Evaluate the safety and tolerability of ALRN-6924 and palbociclib when administered in combination 
The secondary objectives are to: 
• Describe the PK of ALRN-6924 (and its metabolites) and palbociclib when administered in combination 
• Estimate DOR 
• Estimate additional measures of efficacy, including time to response (TTR), PFS, OS, and PFS and OS at 1 year 
The exploratory objective is to: 
• Explore potential markers of response to treatment with ALRN-6924 and palbociclib 
Study Endpoints – Phase 1 dose escalation (ALRN-6924 administered as single agent therapy) 
• Safety and tolerability 
• PK parameters (e.g., area-under-the-curve [AUC], maximum concentration [Cmax], time of Cmax [Tmax], half-life 
[t1/2]) of ALRN-6924 and its metabolites 
• Patient biomarkers (e.g., p53 status, MDM2 and MDMX expression levels), PD biomarkers (e.g., p21, caspase, 
MDM2) in tumor biopsy samples, and PD biomarkers (e.g., MIC-1) in blood samples 
• Anti-tumor effect  
• Incidence of anti-ALRN-6924 antibodies 
• Levels of biomarkers (e.g., p21, p53, caspase) in blood, CTCs, where detectable, or MNCs pre- and post-treatment 
with ALRN-6924. 
Study Endpoints – Phase 2a dose expansion in PTCL (ALRN-6924 administered as single agent therapy) 
• Anti-tumor effect  
• Safety and tolerability 
• PK parameters (e.g., AUC, Cmax, Tmax, and t1/2]) of ALRN-6924 and its metabolites 
• Levels of biomarkers (e.g., p53, MDM2, and MDMX gene sequence and copy number, as well as p21 RNA and/or 
protein expression) in tumor biopsy samples, and in blood, CTCs, where detectable, or MNC samples 
• Incidence of anti-ALRN-6924 antibodies 

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Study Endpoints – Phase 2a dose expansion in MDM2 amplified or MDM2/CDK4 co-amplified solid tumors 
(ALRN-6924 plus palbociclib) 
Primary endpoints: 
• 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). 
• Safety and tolerability including the occurrence of adverse events (AEs) and serious adverse events (SAEs), and 
changes from baseline in vital signs, laboratory analytes, and physical examination findings 
Secondary endpoints: 
• PK parameters, including AUC, Cmax, Tmax, and t1/2 for ALRN-6924, its metabolites, and palbociclib 
• The median time, in months, from the first response of CR or PR to disease progression or death from any cause 
(DOR) 
• The median time, in months, for each of the following: 
- 
The first dose of ALRN-6924 to the first response of CR or PR (TTR) 
- 
The first dose of ALRN-6924 to disease progression or death from any cause (measured at 1 year and 
beyond) (PFS) 
- 
The first dose of ALRN-6924 to death from any cause (measured at 1 year and beyond) (OS) 
Exploratory endpoint: 
• The correlation of response with MDM2, MDMX, and/or CDK4 gene copy number and other genetic and protein 
biomarkers 
Study Design 
This is a Phase 1/2a open-label, multi-center, dose-escalation and dose expansion study designed to evaluate the 
safety, tolerability, PK, PD, and anti-tumor effects of ALRN-6924 administered by IV infusion using up to 
4 different dosing regimens of a 28- or 21-day cycle (alone or in combination), in patients with advanced solid 
tumors or lymphomas with WT TP53 (see p53 Status Determination below). In Phase 1 and Phase 2a, patients will 
receive ALRN-6924 either once weekly for three consecutive weeks for a 28-day cycle (1 and 2 hour infusions may 
be tested) or twice weekly for two consecutive weeks for a 21-day cycle. In Phase 2a, dosing three times a week for 
one week over a 21-day cycle will be tested.  
This study consists of a Phase 1 Dose Escalation Phase (DEP) and a Phase 2a Dose Expansion Phase (EXP).  The 
DEP is a “3+3” dose escalation design to establish the MTD or the OBD of ALRN-6924. The EXP will enroll up to 
5 distinct groups of patients with specific solid tumors and/or lymphomas to further investigate the clinical safety 
profile and potential efficacy of ALRN-6924 at the MTD, OBD, or in alternate dosing regimens.  
In the Phase 2a EXP, peripheral T-cell lymphoma (PTCL) has been selected as one of the diseases to be further 
studied in up to 3 cohorts to identify the optimal dosing regimen.  
Another Phase 2a EXP group will include patients with MDM2 amplified or MDM2/CDK4 co-amplified solid 
tumors who will receive ALRN-6924 in combination with palbociclib.  As these agents have not previously been co-
administered, a safety run-in of 6-8 patients will first be enrolled and evaluated by the sponsor and the primary 
investigators before further patients are permitted to enroll.  Patients will receive ALRN-6924 at the previously 
determined recommended Phase 2 dose for the once-weekly administration schedule (3.1 mg/kg on Days 1, 8, and 
15) and palbociclib at an oral dose of 100 mg daily for 21 days (one dose level below the approved oral dose of 
125 mg) in a 28-day cycle.  Doses of ALRN-6924 and palbociclib may be adjusted for safety or tolerability prior to 
enrolment of additional patients into this EXP group.  
Treatment of patients in the dose escalation and the dose expansion phases of the study will continue until 

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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.  
TP53 Status Determination and Tumor Sampling Requirements 
A central laboratory will be employed to test archived tumor tissue samples or fresh biopsy samples from all patients 
enrolled in the study for TP53 status using Next-Generation Sequencing (NGS).  A fresh biopsy sample will not be 
obtained if such biopsy poses a significant clinical risk to the patient.  To minimize the potential risks from biopsies, 
the healthcare professional performing the biopsy must ensure that any biopsy performed uses a tumor location that 
presents a non-significant risk to the patient.  Likewise, the healthcare professional performing the biopsy must 
choose the biopsy procedure that poses the lowest risk to the patient.  Examples of significant risk procedures would 
include (but are not limited to) surgical biopsies of the brain, lung/mediastinum or pancreas. 
Starting at DEP Dose Level 4, only patients with tumors WT TP53 will be enrolled. This is based on the proposed 
mechanism of action of ALRN-6924, which requires WT p53 protein to be pharmacologically active.  It may be 
possible for some tumor cells to harbor a TP53 mutation on one allele, while maintaining WT TP53 on the second 
allele for TP53 to be pharmacologically active. This hypothesis is supported by in vitro data (unpublished) that 
demonstrated ALRN-6924 potency in a cell line with one WT TP53 allele and one mutated allele, in a substantial 
percentage of cells examined. Furthermore, a patient was recently treated with ALRN-6924 and achieved an 
objective improvement, despite her cancer cells showing only one WT TP53 allele, while lacking any TP53 on the 
second allele (manuscript under review). 
In EXP, beginning with Amendment 6, there will be exceptions from the requirement to obtain central laboratory 
confirmation of WT p53 status prior to enrollment.  The tumor types to be studied during the expansion phase of this 
clinical trial will be among those with high rates of WT TP53, thus enrollment of patients with mutant or deleted 
TP53 will be rare.  Removal of the requirement to await central laboratory results will allow patients with an urgent 
need for treatment to participate in the study without enduring the two week delay that occurs while central 
laboratory testing is performed. Central laboratory testing remains required to confirm WT p53 status.   
Phase 1 – Dose Escalation: 
In the DEP, patients may meet the TP53 requirement through one of the following scenarios (per the exception to 
exclusion criterion 1, patients previously treated with an MDM2-inhibitor are also eligible, provided that a biopsy 
taken after completion of the last treatment with an MDM2-inhibitor meets one of the following): 
• 
Patients may be eligible based on a fresh biopsy or archived tissue that is ≤1 year old. All samples will be 
tested for TP53 status using NGS at the central laboratory. The central laboratory will determine the TP53 
status as expeditiously as possible.  
• 
Upon approval from the medical monitor, patients may also enroll and initiate study treatment based on 
wildtype TP53 status that was determined by another laboratory.  This testing must have been performed on 
tumor samples obtained no more than one year ago. These archived specimens with previously determined 
TP53 status must still be submitted for NGS testing at the central laboratory; the central laboratory’s result 
will determine the patient’s official classification as either TP53 wildtype or TP53 mutant.  
Patients who do not have archived tissue, and for whom a biopsy poses a significant risk, cannot be enrolled. 
Phase 2a – Dose Expansion: 
In the Phase 2a EXP in PTCL, patients may meet the TP53 requirement through one of the following scenarios: 
• 
Patients need to be tested for TP53 status, using a fresh biopsy or archived tissue that is ≤1 year old. 
Archived tissue may be used only if the patient did not receive systemic cytotoxic therapy in the interval 
between tissue collection and the start of treatment with study medication. All samples will be tested for 
TP53 status using NGS at the central laboratory. The central laboratory will determine the TP53 status as 
expeditiously as possible.  Investigators are encouraged to await the TP53 test result, however, if this is 

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clinically deemed not to be in the patient’s best interest, enrollment and the initiation of study treatment 
may proceed, prior to the central laboratory result becoming available. Central laboratory testing is still 
required to confirm WT p53 status.    
• 
Upon approval from the medical monitor, patients may also enroll and initiate study treatment based on 
wildtype TP53 status that was determined by another laboratory.  This testing must have been performed on 
tumor samples obtained no more than one year ago and the patient must not have received systemic 
cytotoxic therapy in the interval since the tissue was obtained. These archived specimens with previously 
determined TP53 status must still be submitted for NGS testing at the central laboratory; the central 
laboratory’s result will determine the patient’s official classification as either TP53 wildtype or TP53 
mutant. 
Patients who do not have archived tissue, and for whom a biopsy poses a significant risk, cannot be enrolled. 
In the Phase 2a EXP cohort in MDM2 amplified or MDM2/CDK4 co-amplified solid tumors (ALRN-6924 plus 
palbociclib): 
• 
Patients must have MDM2 amplified or MDM2/CDK4 co-amplified solid tumors as determined by local, 
commercial or central assays such as NGS, fluorescent in situ hybridization (FISH) or comparative 
genomic hybridization (CGH).  However, all patients must have fresh or archival tissue submitted to the 
central laboratory for NGS testing.  The central laboratory’s results will determine the patient’s official 
classification as MDM2 amplified, MDM2/CDK4 co-amplified, or neither MDM2 amplified nor 
MDM2/CDK4 co-amplified. 
• 
Mutational analysis of TP53 is not required for this cohort, as TP53 mutations are extremely rare among 
patients with MDM2 amplifications.  However, patients with known mutations or deletions of TP53 will be 
excluded from study participation.  Likewise, patients with known retinoblastoma protein (Rb) mutations 
will be excluded. 
Number of Patients to be Enrolled 
Total enrollment of approximately 180 patients is planned for the study.  Approximately 75 patients will be enrolled 
in the DEP for ALRN-6924 as single agent therapy, and approximately 15-25 additional patients for each of the up 
to five expansion cohorts will be enrolled in the EXP.   
Number of Study Sites 
Approximately 15 – 25 clinical sites are planned. 
Eligibility Criteria 
Given the different nature of the individual parts of the protocol, there are 3 distinct sets of inclusion/exclusion 
criteria described in the following for the Phase 1 dose escalation and the expansion cohorts: 
Inclusion Criteria – Phase 1 dose escalation (ALRN-6924 administered as single agent therapy) 
Patients must meet all of the following criteria to be considered for participation in this study. 
1. Male or female patients age 18 years and older, inclusive, at the time of informed consent 
2. Histologically- or cytologically-confirmed solid tumors that are metastatic or unresectable or lymphomas. 
Standard measures do not exist or are no longer effective for these patients. 
3. WT TP53 status for relapsing or treatment-refractory solid neoplasms and lymphomas is mandatory for patients 
enrolling at Dose Level 4 and higher in Stage 1 of the DEP, as well as for all patients enrolled in Stage 2 of the DEP 
or in the EXP. In EXP, beginning with Amendment 6, TP53 status still must be determined by the central laboratory, 
but confirmation of WT TP53 status is not required for enrollment or initiation of study treatment, if the Investigator 
deems it clinically unacceptable to delay treatment.  
4. At least one target lesion that is measurable by either Response Evaluation Criteria in Solid Tumors (RECIST 1.1- 

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See Appendix K) or by Revised International Working Group Response Criteria for lymphoma patients (IWG 2014 
– See Appendix L) 
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (See Appendix A) 
6. Predicted life expectancy of ≥3 months 
7. Adequate hematologic bone marrow function, measured within 7 days prior to the first dose of ALRN-6924, 
defined as: 
• 
Absolute neutrophil count (ANC) ≥1.5 × 109/L 
• 
Hemoglobin ≥9.0 g/dL 
• 
Platelets ≥100 ×109/L 
8. Adequate hepatic function, measured within 7 days prior to the first dose of ALRN-6924, defined as: 
• 
In the absence of disease involvement of the liver: bilirubin ≤1.5 times institutional upper limit of normal 
(ULN), as well as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN  
• 
In the presence of disease involvement of the liver: bilirubin ≤2 times institutional ULN as well as AST and 
ALT ≤5 times ULN  
9. Adequate renal function, measured within 7 days prior to the first dose of ALRN-6924, defined as: 
• 
Urinalysis with no evidence of +2 or higher proteinuria 
• 
Serum creatinine ≤1.5 times institutional ULN, or calculated creatinine clearance ≥50 mL/min (Cockcroft-
Gault formula) 
10. Acceptable coagulation profile, measured within 7 days prior to the first dose of ALRN-6924, defined as: 
• 
Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 times ULN 
• 
Activated partial thromboplastin time (aPTT) ≤1.5 times ULN 
11. Prior anti-cancer therapies must wash-out such that they can neither cause drug-drug interaction with 
ALRN-6924 nor interfere with the anti-cancer evaluation of ALRN-6924.  Therefore, the wash-out has to meet all 
the following criteria: 
- 
 patients must have recovered from the previous therapy to Grade 1 or baseline of significant toxicities, 
excluding alopecia, and  
- 
 5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the prior anti-cancer therapy and 
ALRN-6924 do not interfere with each other’s metabolism, and 
- 
 5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the patient unequivocally 
progressed during the prior anti-cancer therapy 
Palliative radiotherapy for bone lesions ≤2 weeks prior to the first dose of ALRN-6924 is acceptable if acute toxicity 
has resolved 
12. Negative serum or urine pregnancy test within 2 days prior to the first dose of ALRN-6924 for women of child-
bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or who has not been 
naturally post-menopausal for ≥24 consecutive months (i.e., who has had menses any time in the preceding 24 
consecutive months) 
13. All patients (males and females) of child-bearing potential must agree to use an effective method of birth control 
(i.e., latex condom, diaphragm, cervical cap, intra-uterine device [IUD], birth control pill, etc.) beginning two weeks 
prior to the first dose of ALRN-6924 and for 30 days after the last dose of ALRN-6924 
14. Ability to understand and willingness to sign a written informed consent form 
15. Patients with prostate cancer must continue androgen deprivation therapy, unless such therapy was discontinued 
6 months prior to first dose of ALRN-6924 

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Exclusion Criteria – Phase 1 dose escalation (ALRN-6924 administered as single agent therapy) 
Patients who meet any of the following criteria at screening or Day -1 will be excluded: 
1. Previous treatment with investigational agents that inhibit MDM2 or MDMX activity with the following 
exception: 
Patients previously treated with an MDM2-inhibitor are eligible provided that a biopsy taken after 
completion of the last treatment with an MDM2-inhibitor is confirmed as WT TP53 prior to enrollment. 
2. Known hypersensitivity to any study drug component 
3. Known and untreated brain metastases.  Patients with brain metastases that have been treated and demonstrated to 
be clinically stable for ≥30 days may be enrolled.  Patients with primary central nervous system (CNS) malignancies 
are excluded.  
4. Current, clinically significant coagulopathy or platelet disorder, as determined by the Investigator 
5. History of pulmonary embolism within 6 months prior to the first dose of ALRN-6924 or untreated deep venous 
thrombosis (DVT)  
6. Required concurrent use of anti-coagulants or anti-platelet medication, with the exception of aspirin doses ≤ 81 
mg/day, low-dose subcutaneous (SC) heparin or SC low-molecular-weight heparin for DVT prophylaxis, or heparin 
flushes to maintain IV catheter patency. 
7. Patients with pre-existing history of or known cardiovascular risk: 
• 
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) 
• 
Uncontrolled hypertension  
• 
Pre-existing cardiac failure (New York Heart Association Class III-IV) 
• 
Atrial fibrillation on anti-coagulants 
• 
Clinically significant uncontrolled arrhythmias  
• 
Severe valvulopathy 
• 
Corrected QT (QTc) interval on screening electrocardiogram (ECG) ≥450 msec for males and ≥470 msec 
for females (QTc >480 msec for any patient with a bundle branch block) 
8. Clinically significant gastrointestinal bleeding within 6 months prior to the first dose of ALRN-6924 
9. Clinically significant third-space fluid accumulation (e.g., ascites requiring tapping despite the use of diuretics; or 
pleural effusion that requires tapping or is associated with shortness of breath) 
10. Pregnant or lactating females 
11. Evidence of serious and/or unstable pre-existing medical, psychiatric, or other condition (including laboratory 
abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study 
12. Active uncontrolled infection including HIV/AIDS or Hepatitis B or C.  Patients with primary liver cancer that 
have positive hepatitis serology but are not demonstrating active viral hepatitis may be considered for enrollment if 
they meet all other inclusion and no other exclusion criteria. 
13. Starting at Dose Level 4 and higher in Stage 1 of the DEP (as well as for all patients enrolling in Stage 2 of the 
DEP or in the EXP), patients with an Human Papilloma Virus (HPV)-positive malignancy. 
14. Known history of another primary malignancy that has not been in remission for ≥2 years.  Non-melanoma skin 
cancer and cervical carcinomas in situ or squamous intraepithelial lesions (e.g., cervical intraepithelial neoplasia 
[CIN] or prostatic intraepithelial/intraductal neoplasia [PIN]) are allowed. 
15. Any psychological, sociological, or geographical condition that could potentially interfere with compliance with 

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the study protocol and follow-up schedule 
16.  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 infusion with 
ALRN-6924 or within 48 hours after an ALRN-6924 infusion (see Appendix B) 
17.  Hereditary angioedema of any severity or history of severe or life-threatening angioedema due to any cause. 
Inclusion Criteria – Phase 2a dose expansions in PTCL (ALRN-6924 administered as single agent therapy) 
Patients must meet all of the following criteria to be considered for participation in this study. 
1. Male or female patients age 18 years and older at the time of informed consent 
2. A histologically confirmed diagnosis of PTCL based on pathology review at the local institution, using the most 
recent edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues as guidance. 
The pathology sample must be considered to be adequate, meaning that there must be enough well-preserved, 
formalin-fixed biopsy material for the pathologist to be able to perform a morphological and immunohistochemical 
examination so as to in confidence be able to state an unequivocal diagnosis of PTCL. Final diagnoses containing 
caveats such as “suspicious of” or “presumably” are considered inadequate for a patient to be enrolled in the trial. In 
addition, a pathology sample must be available for a potential central pathology read.  
3. Patients must have relapsed or refractory disease after at least one but not more than 7 prior systemic anticancer 
regimen.  
4. Wildtype TP53 status of T-cell lymphoma cells. Beginning with Amendment 6, TP53 status still must be 
determined by the central laboratory, but confirmation of WT TP53 status is not required for enrollment or initiation 
of study treatment, if the Investigator deems it clinically unacceptable to delay treatment. 
5. At least one target lesion that is measurable by Revised International Working Group Response Criteria for 
lymphoma patients (IWG 2014 – See APPENDIX L).  Patients with PTCL subtypes that are assessed by alternative 
criteria must have measurable disease in accordance with those criteria and be approved by the Medical Monitor. 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (See Appendix A) 
7. Predicted life expectancy of ≥3 months 
8. Adequate hematological bone marrow function, measured within 7 days prior to the first dose of ALRN-6924, 
defined as: 
• 
Absolute neutrophil count (ANC) ≥1.0 × 109/L  
• 
Platelets ≥50 ×109/L (platelets <50 x 109/L are acceptable if partly caused by autoimmune destruction 
and/or splenomegaly and/or hepatic disease infiltration) 
 9. Adequate hepatic function, measured within 7 days prior to the first dose of ALRN-6924, defined as: 
• 
Total bilirubin ≤1.5 x upper normal limit, or ≤ 3 x upper normal limit if documented hepatic infiltration 
with lymphoma 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (≤ 5 x 
ULN if documented hepatic infiltration with lymphoma) 
10. Adequate renal function, measured within 7 days prior to the first dose of ALRN-6924, defined as serum 
creatinine ≤1.5 times institutional ULN, or calculated creatinine clearance ≥50 mL/min (Cockcroft-Gault formula) 
11. Acceptable coagulation profile, measured within 7 days prior to the first dose of ALRN-6924, defined as: 
• 
Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 times ULN 
• 
Activated partial thromboplastin time (aPTT) ≤1.5 times ULN 
12. Prior anti-cancer therapies must wash-out such that they can neither cause drug-drug interaction with 
ALRN-6924 nor interfere with the anti-cancer evaluation of ALRN-6924. Therefore, the wash-out has to meet all 

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the following criteria: 
- 
 patients must have recovered from the previous therapy to Grade 1 or baseline of significant toxicities, 
excluding alopecia, and  
- 
 5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the prior anti-cancer therapy and 
ALRN-6924 do not interfere with each other’s metabolism, and 
- 
 5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the patient unequivocally 
progressed during the prior anti-cancer therapy 
Palliative radiotherapy for bone lesions ≤2 weeks prior to the first dose of ALRN-6924 is acceptable if acute toxicity 
has resolved 
13. Negative serum or urine pregnancy test within 2 days prior to the first dose of ALRN-6924 for women of child-
bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or who has not been 
naturally post-menopausal for ≥24 consecutive months (i.e., who has had menses any time in the preceding 24 
consecutive months) 
14. All patients (males and females) of child-bearing potential must agree to use an effective method of birth control 
(i.e., latex condom, diaphragm, cervical cap, intra-uterine device [IUD], birth control pill, etc.) beginning two weeks 
prior to the first dose of ALRN-6924 and for 30 days after the last dose of ALRN-6924 
15. Ability to understand and willingness to sign a written informed consent form 
Exclusion Criteria – Phase 2a dose expansions in PTCL (ALRN-6924 administered as single agent therapy) 
Patients who meet any of the following criteria at screening or Day -1 will be excluded: 
1. Previous treatment with investigational agents that inhibit MDM2 or MDMX activity 
2. Relapse within 75 days of autologous bone marrow transplant. 
3. Prior allogeneic stem cell transplantation, unless immunosuppressants are no longer required and there is no 
active graft versus host disease. 
4. Known central nervous system (CNS) lymphoma [computed tomography (CT) or magnetic resonance imaging 
(MRI) scans are required only if brain metastasis is suspected clinically 
5. Known hypersensitivity to any study drug component 
6. Current, clinically significant coagulopathy or platelet disorder, as determined by the Investigator  
7. Required concurrent use of anti-coagulants or anti-platelet medication, with the exception of aspirin doses 
≤ 81 mg/day, low-dose subcutaneous (SC) heparin or SC low-molecular-weight heparin for DVT prophylaxis, or 
heparin flushes to maintain IV catheter patency.  
8. Patients with pre-existing history of or known cardiovascular risk: 
• 
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) 
• 
Uncontrolled hypertension  
• 
Pre-existing cardiac failure (New York Heart Association Class III-IV) 
• 
Atrial fibrillation on anti-coagulants 
• 
Clinically significant uncontrolled arrhythmias  
• 
Severe valvulopathy 
• 
Corrected QT (QTc) interval on screening electrocardiogram (ECG) ≥450 msec for males and ≥470 msec 
for females (QTc >480 msec for any patient with a bundle branch block) 
9. Clinically significant gastrointestinal bleeding within 6 months prior to the first dose of ALRN-6924 

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10. Clinically significant third-space fluid accumulation (e.g., ascites requiring tapping despite the use of diuretics; 
or pleural effusion that requires tapping or is associated with shortness of breath) 
11. Pregnant or lactating females 
12. Evidence of serious and/or unstable pre-existing medical, psychiatric, or other condition (including laboratory 
abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study 
13. Active uncontrolled infection, including HIV/AIDS or Hepatitis B or C  
14. Known history of another primary malignancy that has not been in remission for ≥1 year.  Non-melanoma skin 
cancer and cervical carcinomas in situ or squamous intraepithelial lesions (e.g., cervical intraepithelial neoplasia 
[CIN] or prostatic intraepithelial/intraductal neoplasia [PIN]) are allowed. 
15. Any psychological, sociological, or geographical condition that could potentially interfere with compliance with 
the study protocol and follow-up schedule 
16.  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 ALRN-6924 
infusion or within 48 hours after an ALRN-6924 infusion (see Appendix B) 
17.  Hereditary angioedema of any severity or history of severe or life-threatening angioedema due to any cause. 
Inclusion Criteria – Phase 2a dose expansion in MDM2 amplified or MDM2/CDK4 co-amplified solid tumors 
(ALRN-6924 plus palbociclib) 
Patients must meet all of the following criteria to be considered for participation in this study:  
1. Histologically-confirmed solid tumor malignancy: 
a. 
For which there is no curative treatment and that is relapsed or refractory, following at least one prior line 
of medical therapy; and 
b. that is either MDM2 amplified or MDM2/CDK4 co-amplified, based on local or central laboratory testing 
by NGS, FISH, or CGH. Tissue must be available for analysis at a central laboratory, even if enrolling 
based on alternative (e.g. local or commercial) test results. Alternative laboratory results require approval 
by the Medical Monitor prior to enrollment.  Specimens must have been obtained after any previous 
exposure to palbociclib or any other CDK4/6 inhibitor. 
2. At least one target lesion that is measurable by RECIST 1.1 or RANO or other appropriate response criteria 
3. Males and females aged 12 years and older   
4. ECOG performance status of 0 to 1 
5. Adequate hematopoiesis, defined as:  
a. 
Absolute neutrophil count (ANC) ≥1.5 × 109/L  
b. Hemoglobin ≥9.0 g/dL (without transfusions in the past 2 weeks) 
c. 
Platelets ≥100 ×109/L  
d. Absolute lymphocyte count ≥ 0.5 × 109/L 
6. Adequate hepatic function, defined as:  
a. 
In the absence of disease involvement of the liver: bilirubin ≤1.5 times institutional upper limit of normal 
(ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN   
b. In the presence of disease involvement of the liver: bilirubin ≤2 times institutional ULN and AST and ALT 
≤5 times ULN   
7. Adequate renal function, defined as serum creatinine ≤1.5 times institutional ULN, or calculated creatinine 
clearance ≥50 mL/min (Cockcroft Gault formula) 
8. Five half-lives or 4 weeks, whichever is shorter, must have elapsed since any prior anticancer agent was 

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administered, unless the patient unequivocally progressed during that therapy and the agent would not be 
expected to interfere with ALRN-6924 or palbociclib metabolism or impede clinical assessments 
9. Recovery from the acute toxic effects of all prior therapies to ≤ Grade 1 or baseline, excluding alopecia 
10. Provision of informed consent and, where applicable, pediatric assent 
11. Agreement to use acceptable methods of pregnancy prevention, if of child-bearing potential 
Exclusion Criteria – Phase 2a dose expansion in MDM2 amplified or MDM2/CDK4 co-amplified solid tumors 
(ALRN-6924 plus palbociclib) 
Patients who meet any of the following criteria at screening or Day -1 will be excluded: 
1. Tumors with known mutations or deletions in TP53 or Rb  
2. Known hypersensitivity to any component of study medication 
3. Symptomatic or untreated CNS metastases  
4. Pulmonary embolism within the past 6 months or DVT that has not been fully treated. 
5.  Clinically significant cardiovascular risk factors, including: 
• 
myocardial infarction, unstable angina, coronary artery bypass grafting, stenting, angioplasty, or acute 
coronary syndrome in the past 6 months 
• 
New York Heart Association Class III or IV heart failure 
• 
clinically significant uncontrolled arrhythmia 
• 
corrected QT (QTc) interval ≥450 msec for males and ≥470 msec for females (QTc >480 msec for any 
patient with a bundle branch block) 
6. Uncontrolled hypertension 
7. Active, uncontrolled infection, including HIV, hepatitis B, or hepatitis C  
8. Human papilloma virus (HPV)-positive malignancy. 
9. Ascites requiring paracentesis or pleural effusion requiring pleurocentesis or causing dyspnea  
10. Hereditary angioedema of any severity or history of clinically significant angioedema, due to any cause 
11. Major surgery within 3 weeks prior to the first dose of ALRN-6924   
12. History of another malignancy within the past year, excluding nonmelanoma skin cancers, carcinomas in situ, or 
other malignancies with ≥ 95% 5-year survival  
13. Pregnant or lactating females 
14. Required use of medications that are primarily cleared by hepatobiliary transporters, including organic anion 
transporters, OATP1B1 and OATP1B3, and bile salt export pump (BSEP), unless administration is not required 
on the day of or within 48 hours following ALRN-6924 administration 
15. Required use of medications that are strong inhibitors or moderate to strong inducers of CYP3A 
16. Administration of any investigational agent, regardless of indication, within the 2 weeks prior to enrollment, 
unless a minimum of 5 half-lives have elapsed 
17. Any medical, psychological, or social condition that would interfere with patient safety or the conduct of the 
study 
Starting Dose, Dose Escalation, and Dose Reduction 
All patients will be dosed with ALRN-6924 at a pre-defined level based on body weight as measured on Day 1 (or 
up to 3 days prior to Day 1) of each cycle.  
 

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Phase 1 – Dose Escalation  
Starting at Dose Level (DL) 3 in dose escalation, patients will be sequentially assigned to a treatment arm: Dose 
Regimen (DR) A will continue testing administration of ALRN-6924 once per week, or Dose Regimen (DR) B 
testing administration of ALRN-6924 twice per week.  For Dose Level 3, DR- A will be enrolled first, DR-B will be 
enrolled second. The starting dose (DL1) in DEP, based on results from nonclinical toxicology assessments, will be 
0.16 mg/kg.   
Dose Level and Dose Regimen Schematic – DEP 
 
During the first 2 dose levels, patients will receive ALRN-6924 on Days 1, 8, and 15 of a 28-day cycle.  Starting 
with DL 3, patients in DR- A will continue being treated once a week on Days 1, 8, and 15 of a 28-day cycle, 
whereas patients in DR- B will be treated twice a week, on Days 1, 4, 8, and 11 of a 21-day cycle. Starting at DL 
7A, a modified infusion regimen (DR-A-2) will be explored to mitigate potential infusion reactions.  
Treatment 
Regimen 
Infusion Days 
Infusion Time 
Additional notes 
DR-A 
1, 8, 15 of a 
28-day cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or oral 
fluids (500mL – 1000 mL) should be administered 
unless clinically contraindicated. 
DR-A-2 
1, 8, 15 of a 
28-day cycle 
2 hours (±15 min) 
At the end of the infusion, IV fluids (saline) or oral 
fluids (500mL – 1000 mL) should be administered 
unless clinically contraindicated. Administer 
dexamethasone (4 mg orally or IV) approximately 4 
hours after the end of the infusion in Cycles 1 and 2, 
and thereafter at the discretion of the investigator.  
DR-B 
1, 4, 8, 11 for 
DR-B of a 
21-day cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or oral 
fluids (500mL – 1000 mL) should be administered 
unless clinically contraindicated. 
A 2-stage dose escalation design will be employed.  During the initial Stage 1 Escalation Phase, 100% dose 
increments will be utilized until ≥1 of 3 patients in a cohort experiences any Grade ≥2 AE that is at least possibly 
related to study drug.  In Stage 2, dose escalation will continue using 3-patient cohorts and the modified Fibonacci 
sequence (i.e., 67%, 50%, 40%, 33%), until the MTD or an OBD is established. A drug-related AE is an event that is 

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possibly, probably or definitely attributed to ALRN-6924. Grading of AEs will be defined by the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 (See Appendix O).  As drug-related AEs Grade ≥2 
occurred in DL-4A (fatigue) and in DL-3B (neutropenia), subsequent dose escalations with DL-5A and DL-4B 
continued using modified Fibonacci sequence (i.e., 67%, 50%, 40%, and 33%).   
Escalation to the next dose level within each DR may proceed in the absence of DLT at the completion of Cycle 1 
(treatment cycle = 28 days for DR-A, DR-A-2 and 21 days for DR-B). Escalation to the next dose level within each 
DR as well as the DR and DL for the EXP cohorts will be decided by a Safety Review Committee (SRC), consisting 
of the Principal Investigators and Sponsor’s Medical Monitor, which will review all available safety information 
from all patients. As two DLTs have occurred in DR-7A (hypotension and hepatobiliary laboratory abnormalities), 
there will be no further escalation in DR-A. A new modified infusion regimen was tested (DR-A-2) starting at DR-
7A-2.  As two DLTs have occurred in DR-7A-2 (anemia and neutropenia), there will be no further escalation in DR-
A-2. 
Based on review of available safety and PK data during this and other studies with ALRN-6924, dose escalation or 
modification steps may be adjusted (i.e. increased or decreased) by the SRC to limit the number of patients exposed 
to sub-therapeutic dose levels as well as to ensure patients’ safety.  
Within each Dose Regimen cohort: 
- 
If no DLT is observed in a cohort, the subsequent patient group will be enrolled at the next planned dose 
level of that dose regimen.  
- 
If a DLT is observed in ≥2 of 3 patients at any dose level, no further dose escalation will occur in that DR, 
and the current dose will be defined as the maximum administered dose (MAD).   
- 
If a DLT is observed in 1 of 3 patients in a cohort at any dose level, then up to 6 patients total will be 
enrolled in the same DR at that dose level.  If a DLT is observed in 2 or more patients in the expanded 
cohort, then no further dose escalation will occur, and the current dose will be defined as the MAD, unless 
the SRC decides that there is sufficient clinical uncertainty about the DLTs that warrants the enrollment of 
up to 6 additional patients.  In the event of additionally enrolled patients, if a DLT is observed in 33% or 
more DLT-evaluable patients in the entire cohort, then no further dose escalation will occur, and the current 
dose will be defined as the MAD for the dosing regimen under consideration.   
- 
After the MAD is defined, either the previously administered lower dose will be expanded to a total of 6 
patients, or an intermediate dose (between the MAD and the previous dose level) will be investigated in a 
total of 6 patients.  The highest dose tolerated in at least 5 of 6 patients (i.e. <33% of DLT-evaluable 
patients experiencing a DLT) will be defined as the MTD or OBD. Additional patients may be added to 
further explore the MTD or OBD prior to expansion.  
The SRC may hold the dose (e.g., stop dose escalation) at their discretion and enroll additional patients until 
sufficient safety data are obtained to determine escalation of the current dose level or to confirm a certain dose level 
as an MTD or OBD. 
Dose Level and Dose Regimen – Phase 2a dose expansions  
Based on the safety, efficacy and PK/PD profile of ALRN-6924 from the dose escalation portion of the study as well 
as data from other clinical trials and preclinical data, three dosing regimens of ALRN-6924 administered as single 
agent therapy (DR-A, DR-B, DR-C) will be tested in Phase 2a EXP in PTCL to determine the optimal dosing 
regimen.  
For patients with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors, patients will receive ALRN-6924 in 
combination with palbociclib.  Palbociclib will be administered at an oral dose of 100 mg daily (Days 1-21) in 
combination with ALRN-6924, which will be administered at 3.1 mg/kg on Days 1, 8, and 15 of a 28-day cycle (or 
as otherwise determined during the safety run-in period for this cohort).   
The decision to begin palbociclib below the approved dose level of 125 mg is based on the frequency of required 

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dose reductions, often due to neutropenia.  The SRC may consider escalating to the approved palbociclib dose, if 
palbociclib-related toxicities are not prohibitive and patient benefit is expected to outweigh risk.   
Dose Level and Dose Regimen – Phase 2a dose expansions: 
Treatment 
Regimen 
Drug and 
Dose Level 
Infusion 
Days 
Infusion Time 
Additional notes 
DR-A 
ALRN-6924 
3.1 mg/kg 
1, 8, 15 of 
a 28-day 
cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically contraindicated. 
DR-B 
ALRN-6924 
2.7 mg/kg 
1, 4, 8, 11 
of a 21-
day cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically contraindicated. 
DR-C 
ALRN-6924 
3.1 mg/kg  
[If 3.1 mg/kg 
is not well 
tolerated, 
lower doses 
may be tested 
starting at 
dose levels 
of -25%]   
1, 3, 5 of a 
21-day 
cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically contraindicated. 
Combination 
with 
palbociclib 
ALRN-6924 
3.1 mg/kg 
[If 3.1 mg/kg 
is not well 
tolerated, up 
to two dose 
reductions of 
25% may be 
tested]   
1, 8, 15 of 
a 28-day 
cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically contraindicated. 
 
Palbociclib 
100 mg 
[If 100 mg is 
not well 
tolerated, a 
reduced dose 
of 75 mg may 
be tested.] 
1-21 of a 
28-day 
cycle 
Oral 
Palbociclib should be administered with food.  
On days when both drugs are administered 
(Days 1, 8, and 15 of each cycle), palbociclib 
should be administered at least 6 hours after the 
infusion of ALRN-6924.  
Intra-patient Dose Escalation – Phase 1 Dose Escalation 
A patient’s dose may be increased to that of a cohort that completed the first cycle without dose-limiting toxicity in 
≥33% of DLT-evaluable patients and that has not exceeded the MTD.  Intra-patient dose escalations will be allowed 
provided that the patient completed at least two treatment cycles and did not experience study medication-related 
toxicity greater than Grade 2 (except for alopecia, electrolyte disturbances responsive to correction within 24 hours, 

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diarrhea, nausea, fatigue and vomiting that responds to standard medical care).  Approval for intra-patient dose 
escalation must be obtained from the Medical Monitor. 
Dose Modifications – Phase 1 dose escalation (ALRN-6924 administered as single agent therapy) 
In the event a Grade 4 AE considered related to ALRN-6924 is observed, the patient must be discontinued from the 
study. Exceptions include Grade 4 neutropenia lasting <3 days, and emesis, diarrhea or electrolyte abnormalities that 
resolve within 2 days on optimum treatment.  For these exceptions, treatment may be delayed for up to 2 weeks to 
allow resolution of the toxicity (i.e., return to Grade ≤1 or baseline), followed by re-treatment at a reduced dose.  
Two dose reductions are permitted, a third dose reduction will require evidence of clinical benefit and approval by 
the Medical Monitor.   Relevant labs should be repeated as medically indicated.   
In the event a Grade 3 AE considered related to ALRN-6924 is observed (exceptions are Grade 3 fatigue, nausea, 
emesis, diarrhea or clinically insignificant electrolyte abnormalities that resolve within 2 days on optimum 
treatment), treatment may be delayed for up to 2 weeks to allow resolution of the toxicity, followed by re-treatment 
at a reduced dose.  Two dose reductions are permitted, a third dose reduction will require evidence of clinical benefit 
and approval by the Medical Monitor. Relevant labs should be repeated as medically indicated.   
Following related Grade 3 and Grade 4 AEs (as permitted), the dose for re-treatment will be reduced by 25% 
intervals (e.g., if the dose is 3.1 mg/kg, the dose will be reduced sequentially to 2.3 mg/kg and 1.7 mg/kg).   
For other clinically significant AEs, treatment may be delayed by up to 2 weeks to allow for the resolution of AEs to 
an acceptable level, and a dose reduction may be made as described above at the discretion of the Investigator in 
consultation with Sponsor’s Medical Monitor.  If a patient experiences multiple AEs, decisions on dosing delay or 
dose reduction will be based on the most severe AE.  Any patient who experiences recurrent, clinically significant 
AEs after one dose reduction may undergo one additional dose reduction.  Patients who continue to experience 
clinically significant AEs after a 2-week delay or the maximum allowed number of dose reductions will be 
discontinued from study treatment. 
Adverse events considered for dose reduction should not include events assessed by the Investigator as exclusively 
related to underlying disease or other medical condition or concomitant treatment.  A patient who experiences an AE 
considered related to ALRN-6924 that does not meet the requirement for discontinuation may continue on study if 
the patient is receiving clinical benefit and/or the Investigator feels continued participation is in the best interest of 
the patient.  In such cases, at the Investigator’s discretion and in agreement with Sponsor’s Medical Monitor, the 
dose for a patient may be reduced as described above.   
A patient who experiences a DLT must continue treatment at a reduced dose level, or discontinue ALRN-6924 
treatment (if Grade 4 related AE), as described above at the discretion of the Investigator and in agreement with 
Sponsor’s Medical Monitor until disease progression or unacceptable toxicity. Once the dose has been reduced for a 
patient, it may not be re-escalated. 
Dose Modifications – Phase 2a dose expansions in PTCL (ALRN-6924 administered as single agent therapy) 
In the event a non-hematologic Grade 4 AE considered related to ALRN-6924 is observed, the patient must be 
discontinued from the study. Exceptions include emesis, diarrhea or electrolyte abnormalities that resolve within 2 
days on optimum treatment.  For these exceptions, treatment may be delayed for up to 2 weeks to allow resolution of 
the toxicity (i.e., return to Grade ≤1 or baseline), followed by re-treatment at a reduced dose. Relevant labs should 
be repeated as medically indicated.   
In the event a non-hematologic Grade 3 AE considered related to ALRN-6924 is observed (exceptions are Grade 3 
fatigue, nausea, emesis, diarrhea or clinically insignificant electrolyte abnormalities that resolve within 2 days on 
optimum treatment), treatment may be delayed for up to 2 weeks to allow resolution of the toxicity, followed by re-
treatment at a reduced dose. Relevant labs should be repeated as medically indicated.  
 

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For hematologic toxicities, patients must discontinue treatment with ALRN-6924 if  
• 
Neutrophil counts < 0.5 x 109/L for > 5 days, or 
• 
Platelet counts < 10 x 109/L, or 
• 
Hemoglobin < 6 g/dL (despite RBC transfusion or Erythropoiesis-Stimulating Agent (ESA) administration) 
Patients interrupt treatment if  
• 
Neutrophil counts < 0.5 x 109/L for ≤ 5 days, or 
• 
Platelet counts < 25 x 109/L and >10 x 109/L, or 
• 
Hemoglobin < 8 g/dL and > 6 g/dL 
After resolution of hematologic toxicity (i.e., return to Grade ≤1 or baseline), patients may continue at a reduced 
dose. Relevant labs should be repeated as medically indicated.  
Following related Grade 3 and Grade 4 AEs (as permitted), the dose for re-treatment will be reduced by 25% 
intervals (e.g., if the dose is 3.1 mg/kg, the dose will be reduced sequentially to 2.3 mg/kg and 1.7 mg/kg).  Two 
dose reductions are permitted, a third dose reduction will require evidence of clinical benefit and approval by the 
Medical Monitor.  
Dose Modifications – Phase 2a dose expansion in MDM2 amplified or MDM2/CDK4 co-amplified solid 
tumors (ALRN-6924 plus palbociclib) 
Dose modifications of ALRN-6924 will be as described above for the Phase 1 dose escalation. Dose modifications 
of palbociclib are to be made in accordance with the current approved US prescribing information. In the event that 
palbociclib administration must be discontinued, the patient may continue to receive ALRN-6924 as a study 
participant until a criterion for treatment discontinuation has been met. However, if discontinuation of ALRN-6924 
is required, patients will be considered to have discontinued study treatment. These patients may continue to receive 
palbociclib treatment at the investigator’s discretion. 
Dose Limiting Toxicity Definition during Phase 1 Dose Escalation  
A DLT will be defined as any Grade ≥3 AE that is considered possibly, probably, or definitely related to the study 
drug, with the following exceptions: (1) for fatigue, nausea, emesis, diarrhea or mucositis, only Grade ≥3 AE that do 
not respond within 48 hours to standard supportive/pharmacological treatment will be considered DLT; (2) for 
electrolyte imbalances, only Grade ≥3 AE that do not respond to correction within 24 hours will be considered DLT; 
(3) for infusion reactions, only a Grade 3 reaction which caused hospitalization or Grade 4 will be considered DLT.  
In addition, specific hematologic DLTs are defined as:  
• Thrombocytopenia – Grade 4 of any duration, Grade 3 for ≥7 days, or Grade 3 associated with clinically 
significant bleeding 
• Neutropenia – Grade 4 for ≥3 days, or any Grade ≥3 febrile neutropenia  
The above criteria will be used to make individual patient determinations regarding dose reductions, interruptions or 
discontinuation throughout the course of the trial, but DLTs occurring during Cycle 1 will be used to inform safety 
and tolerability assessments for dose escalation decisions. 
Study Drug Administration 
ALRN-6924 will be administered as an IV infusion as follows: 
Phase 1 Dose Escalation (ALRN-6924 administered as single agent therapy): 
• 
Dose Levels 1 and 2 Dose Regimen A on Days 1, 8, and 15 of each 28-day cycle (1 hour infusion) 
• 
Dose Levels 3 and beyond as follows –  
o Dose Regimen A on Days 1, 8, and 15 in a 28-day cycle (1 hour infusion) 

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o Dose Regimen B on Days 1 and 4, 8 and 11 in a 21-day cycle (1 hour infusion) 
o Dose Regimen A-2 on Days 1, 8, and 15 in a 28-day cycle (2 hour infusion) [starting with Dose Level 7] 
Patients who remain on study treatment for 2 years or longer may have their dosing frequency reduced, at the 
discretion of the investigator (i.e., Days 1 and 15 of a 28-day cycle (DR-A) or Days 1 and 8 of a 21-day cycle 
(DR-B).  In the event that disease control is not maintained, the original dosing schedule may be resumed.   
Phase 2a Dose Expansion in PTCL (ALRN-6924 administered as single agent therapy): 
• 
Dose Regimen A 3.1 mg/kg on Days 1, 8, and 15 in a 28-day cycle (1 hour infusion)  
• 
Dose Regimen B 2.7 mg/kg on Days 1 and 4, 8 and 11 in a 21-day cycle (1 hour infusion) 
• 
Dose Regimen C 3.1 mg/kg on Days 1, 3 and 5 in a 21-day cycle (1 hour infusion). [If 3.1 mg/kg is not 
well tolerated, lower doses may be tested starting at dose levels  of -25%]   
Phase 2a Dose Expansion in MDM2 amplified or MDM2/CDK4 co-amplified solid tumors (ALRN-6924 plus 
palbociclib): 
• 
ALRN-6924: 3.1 mg/kg (1 hour infusion) on Days 1, 8, and 15 in a 28-day cycle plus palbociclib: 100 mg 
per day orally on Days 1-21 in the same 28-day cycle. It is recommended that palbociclib be administered 
with food. On days when both drugs are administered (Days 1, 8, and 15 of each cycle), palbociclib should 
be administered at least 6 hours after the infusion of ALRN-6924.  
Following the administration of each dose of ALRN-6924, patients must receive 500 to 1000 mL of IV or oral 
fluids, unless clinically contraindicated. 
Statistical Methods 
For each phase of study, results will be summarized by dose level and regimen.  Tabulations will be produced for 
appropriate demographic and baseline clinical characteristics, efficacy, pharmacokinetic, and safety parameters.  For 
categorical variables, summary tabulations of the number and percentage of patients within each category of the 
parameter will be presented.  For continuous variables, the number of patients, mean, median, standard deviation, 
minimum, and maximum values will be presented.  Time-to-event data will be summarized using Kaplan-Meier 
methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 95% confidence intervals.  
Graphical displays will be presented, as appropriate. Results will be evaluated for all patients.   
 

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TABLE OF CONTENTS 
INVESTIGATOR’S SIGNATURE PAGE ................................................................................................... 2 
ALRN-6924-1-01 SYNOPSIS ...................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................................ 21 
LIST OF TABLES ...................................................................................................................................... 25 
LIST OF FIGURES .................................................................................................................................... 25 
ACRONYM LIST ....................................................................................................................................... 26 
1 
BACKGROUND AND STUDY RATIONALE ................................................................................ 29 
1.1 
Therapeutic Rationale for Inhibiting MDM2/MDMX to Restore p53 Activity .................... 29 
1.2 
Stapled Peptide Technology .................................................................................................. 30 
1.3 
ALRN-6924 ........................................................................................................................... 30 
1.4 
Nonclinical Experience with ALRN-6924 ............................................................................ 30 
1.4.1 
Pharmacology ........................................................................................................................ 30 
1.4.2 
Toxicology and Nonclinical Safety ....................................................................................... 31 
1.4.3 
Pharmacokinetics and Absorption, Distribution, Metabolism and Excretion ....................... 33 
1.4.4 
ALRN-6924 Administered in Combination with Palbociclib ............................................... 34 
1.5 
Clinical Experience with ALRN-6924 .................................................................................. 41 
1.6 
Clinical Experience with Palbociclib .................................................................................... 41 
2 
STUDY OBJECTIVES ...................................................................................................................... 42 
2.1 
Phase 1 Dose Escalation (ALRN-6924 administered as single agent therapy) ..................... 42 
2.1.1 
Primary Objectives ................................................................................................................ 42 
2.1.2 
Secondary Objectives ............................................................................................................ 42 
2.1.3 
Exploratory Objectives .......................................................................................................... 42 
2.2 
Phase 2a Dose Expansion (ALRN-6924 administered as single agent therapy) ................... 42 
2.2.1 
Primary Objectives ................................................................................................................ 42 
2.2.2 
Secondary Objectives ............................................................................................................ 42 
2.2.3 
Exploratory Objectives .......................................................................................................... 43 
2.3 
Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 Co-amplified Solid 
Tumors (ALRN-6924 plus palbociclib) ............................................................................... 43 
2.3.1 
Primary Objectives ................................................................................................................ 43 
2.3.2 
Secondary Objectives ............................................................................................................ 43 
2.3.3 
Exploratory Objective ........................................................................................................... 43 
3 
INVESTIGATIONAL PLAN ............................................................................................................ 44 

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3.1 
Study Rationale ..................................................................................................................... 44 
3.2 
Study Overview ..................................................................................................................... 44 
3.2.1 
Pharmacokinetic, Pharmacodynamic, and Clinical Activity Assessments............................ 47 
3.3 
Number of Patients and Centers ............................................................................................ 49 
3.4 
Duration of Study .................................................................................................................. 49 
4 
PATIENT POPULATION ................................................................................................................. 50 
4.1 
Inclusion Criteria – Phase 1 dose escalation (ALRN-6924 administered as single agent 
therapy) ................................................................................................................................ 50 
4.2 
Exclusion Criteria – Phase 1 dose escalation (ALRN-6924 administered as single agent 
therapy) ................................................................................................................................ 51 
4.3 
Inclusion Criteria – Phase 2a dose expansions in PTCL (ALRN-6924 administered as single 
agent therapy) ....................................................................................................................... 53 
4.4 
Exclusion Criteria – Phase 2a dose expansions in PTCL (ALRN-6924 administered as single 
agent therapy) ....................................................................................................................... 55 
4.5 
Inclusion Criteria - Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 
Co-amplified Solid Tumors (ALRN-6924 plus palbociclib) ................................................ 56 
4.6 
Exclusion Criteria - Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 
Co-amplified Solid Tumors (ALRN-6924 plus palbociclib) ................................................ 57 
4.7 
Removal of Patients from Study Therapy ............................................................................. 58 
4.8 
Patient Replacement .............................................................................................................. 58 
5 
TREATMENT PLAN ........................................................................................................................ 59 
5.1 
Study Drug Description ......................................................................................................... 59 
5.2 
Preparation of ALRN-6924 ................................................................................................... 59 
5.3 
Study Drug Administration ................................................................................................... 59 
5.4 
Management of Toxicities ..................................................................................................... 62 
5.4.1 
Toxicities Related to ALRN-6924 ........................................................................................ 62 
5.4.2 
Toxicities Related to Palbociclib ........................................................................................... 64 
5.5 
Registering and Enrolling Patients on Study, Assignment of Dose Level ............................ 64 
5.5.1 
Patient Registration ............................................................................................................... 64 
5.5.2 
Staggered Cohort Enrollment Scheme for Dose Level 1 (DEP) ........................................... 64 
5.5.3 
Assignment of Dose Level (DEP) ......................................................................................... 64 
5.6 
Dose Escalation Criteria (DEP) ............................................................................................. 64 
5.7 
Planned Dose Levels ............................................................................................................. 65 
5.7.1 
Dose Levels for the Dose Escalation Portion of the Study ................................................... 65 

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5.7.2 
Dose Levels for the Expansion Portion of the Study ............................................................ 66 
5.7.3 
Intra-Patient Dose Escalation- Phase 1 Dose Escalation ....................................................... 67 
5.8 
Dose and Schedule Adjustments for Toxicity ....................................................................... 68 
5.8.1 
Dose Modifications – Phase 1 dose escalation (ALRN-6924 administered as single agent 
therapy).................................................................................................................................. 68 
5.8.2 
Dose Modifications – Phase 2a dose expansions in PTCL (ALRN-6924 administered as 
single agent therapy) ............................................................................................................. 69 
5.8.3 
Dose Modifications – Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 Co-
amplified Solid Tumors (ALRN-6924 plus palbociclib)....................................................... 69 
5.9 
Toxicity, DLT and MTD Evaluation ..................................................................................... 70 
5.9.1 
Toxicity Grading Criteria ...................................................................................................... 70 
5.9.2 
Definition of Dose-Limiting Toxicity ................................................................................... 70 
5.9.3 
Definition of Maximum Tolerated Dose ............................................................................... 70 
5.9.4 
Definition of Optimal Biological Dose (OBD) ..................................................................... 70 
5.10 
Concomitant Medications and Therapies .............................................................................. 70 
5.10.1 Permitted and Recommended Medications ........................................................................... 70 
5.10.2 Prohibited Medications and Medications Requiring Special Consideration ......................... 71 
5.11 
Packaging, Labeling, and Storage ......................................................................................... 71 
5.12 
Drug Accountability .............................................................................................................. 71 
6 
STUDY PROCEDURES.................................................................................................................... 73 
6.1 
Schedule of Study Events ...................................................................................................... 73 
6.2 
Informed Consent and Pediatric Assent ................................................................................ 73 
6.3 
Biopsies ................................................................................................................................. 73 
6.4 
Germline DNA ...................................................................................................................... 74 
6.5 
Medical and Disease History ................................................................................................. 74 
6.6 
Vital signs .............................................................................................................................. 74 
6.7 
Electrocardiograms ................................................................................................................ 74 
6.8 
Physical Examination ............................................................................................................ 74 
6.9 
Laboratory Assessments ........................................................................................................ 74 
6.10 
Disease Assessments/Imaging ............................................................................................... 75 
6.11 
Concomitant Medications ..................................................................................................... 75 
6.12 
PK and PD Assessments ....................................................................................................... 75 
6.13 
End of Treatment and End of Study ...................................................................................... 79 

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7 
STATISTICAL CONSIDERATIONS ............................................................................................... 80 
7.1 
General Considerations ......................................................................................................... 80 
7.2 
Patient Disposition and Characteristics ................................................................................. 80 
7.3 
Safety Analysis ...................................................................................................................... 80 
7.4 
Pharmacokinetic Analysis ..................................................................................................... 80 
7.5 
Pharmacodynamic Analysis .................................................................................................. 80 
7.6 
Clinical Activity Analysis ..................................................................................................... 80 
8 
SAFETY ............................................................................................................................................. 82 
8.1 
Adverse Event Definitions .................................................................................................... 82 
8.1.1 
Adverse Event ....................................................................................................................... 82 
8.1.2 
Serious Adverse Event .......................................................................................................... 82 
8.1.3 
Unexpected Adverse Event ................................................................................................... 83 
8.2 
Adverse Event Reporting Period ........................................................................................... 83 
8.3 
Recording of Adverse Events ................................................................................................ 83 
8.3.1 
Maximum Intensity ............................................................................................................... 84 
8.3.2 
Relationship to Study Treatment ........................................................................................... 84 
8.4 
Adverse Event Reporting ...................................................................................................... 85 
8.5 
Adverse Event and Serious Adverse Event Follow-Up ........................................................ 86 
8.6 
Ongoing Safety Evaluation ................................................................................................... 86 
8.7 
Pregnancy .............................................................................................................................. 86 
8.8 
Medication Errors .................................................................................................................. 87 
8.9 
Overdose................................................................................................................................ 87 
8.10 
Data and Safety Review Process ........................................................................................... 87 
8.10.1 Review Process ..................................................................................................................... 87 
8.10.2 Oversight Responsibilities ..................................................................................................... 88 
9 
STUDY MANAGEMENT ................................................................................................................. 89 
9.1 
Investigator Responsibilities ................................................................................................. 89 
9.1.1 
Data Management ................................................................................................................. 89 
9.1.2 
Protocol Adherence ............................................................................................................... 89 
9.1.3 
Study Drug Accountability .................................................................................................... 89 
9.2 
Monitoring ............................................................................................................................. 89 
9.3 
Audits and Inspections .......................................................................................................... 89 
9.4 
Protocol Amendments ........................................................................................................... 90 

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9.5 
Record Keeping ..................................................................................................................... 90 
9.5.1 
Health Insurance Portability Accountability Act of 1996 ..................................................... 90 
9.5.2 
Financial and Regulatory Disclosures ................................................................................... 90 
9.5.3 
Access to Original Records ................................................................................................... 90 
9.5.4 
Retention of Study Documents.............................................................................................. 90 
10 
ETHICAL CONSIDERATIONS ....................................................................................................... 91 
10.1 
Informed Consents and Pediatric Assents ............................................................................. 91 
10.2 
Institutional Review Board .................................................................................................... 91 
10.3 
Confidentiality ....................................................................................................................... 91 
11 
ADMINISTRATIVE STRUCTURE OF THE STUDY .................................................................... 93 
12 
REFERENCES ................................................................................................................................... 94 
LIST OF TABLES 
Table 1: 
Pharmacokinetic Studies Completed with ALRN-6924 ........................................................ 33 
Table 2: 
Pharmacokinetic Parameters of ALRN-6924 and Palbociclib when Administered Alone or 
in Combination in Nu/nu Mice .............................................................................................. 41 
LIST OF FIGURES 
Figure 1: 
Effect of ALRN-6924 on Tumor Growth in the MCF-7 Breast Cancer Xenograft Model ... 31 
Figure 2: 
Dose-dependent Platelet Response in 4-week Monkey GLP Toxicity Study ....................... 32 
Figure 3: 
Combined Mechanism of Action of ALRN-6924 and Palbociclib ....................................... 35 
Figure 4: 
Co-amplification of MDM2 and CDK4 ................................................................................ 36 
Figure 5: 
Effect of ALRN-6924 ± Palbociclib on In Vitro Proliferation of MDM2/CDK4-co-amplified 
SJSA1 Osteosarcoma Cancer Cells ....................................................................................... 37 
Figure 6: 
Mechanism of Enhancement of Anti-proliferative Effects of ALRN-6924 when Combined 
with Palbociclib ..................................................................................................................... 38 
Figure 7: 
Effect of Combination of ALRN-6924 and Palbociclib on Tumor Growth in MCF-7 and 
SJSA1 Mouse Xenograft Models .......................................................................................... 39 
Figure 8: 
Plasma Concentrations of ALRN-6924 and Palbociclib when Administered Alone or in 
Combination in Nu/nu Mice .................................................................................................. 41 
Figure 9: 
Dose Level and Dose Regimen Schematic ............................................................................ 65 
 
 

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ACRONYM LIST 
ACE 
 angiotensin converting enzyme 
AE 
 adverse event 
AIDS 
 acquired immunodeficiency syndrome 
ALT (SGPT) 
 alanine aminotransferase 
ANC 
 absolute neutrophil count 
aPTT 
 activated partial thromboplastin time 
ARB 
 angiotensin-receptor blocker 
AST (SGOT) 
 aspartate aminotransferase 
AUC 
 area under the curve 
BCRP 
 breast cancer resistance protein 
β-hCG  
 Beta human chorionic gonadotropin 
BrdU 
 5′-bromo-2′-deoxyuridine (thymidine analog) 
BSEP 
 bile salt export pump 
BUN 
 blood urea nitrogen 
CDK4 
 cyclin-dependent kinase 4 
cfDNA 
 cell free DNA 
CFR 
 Code of Federal Regulations 
CGH 
 comparative genomic hybridization 
CIN 
 cervical intraepithelial neoplasia 
Cmax 
 maximum concentration 
CNS 
 central nervous system 
CO2 
 carbon dioxide 
CR 
 complete response 
CT 
 computed tomography 
CTC 
 circulating tumor cells 
CTCAE 
 Common Terminology Criteria for Adverse Events 
CYP 
 cytochrome P450 
D5W 
 5% dextrose in water 
DEP 
 dose escalation phase 
DL 
 dose level 
DLT 
 dose-limiting toxicity 
DNA 
 deoxyribonucleic acid 
DOR 
 duration of response 
DR 
 dose regimen 
DRF 
 dose range finding 
DVT 
 deep vein thrombosis 
ECG 
 electrocardiogram 
ECOG 
 Eastern Cooperative Oncology Group 
eCRF 
 electronic case report form 
EOI 
 end of infusion 
ESA 
 Erythropoiesis-Stimulating Agent 
EXP 
 expansion phase 

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FDA 
 Food and Drug Administration 
FDG 
 [18F]-fluorodeoxyglucose 
FISH 
 fluorescent in situ hybridization 
FOXM1 
 Forkhead box protein M1 
GCP 
 good clinical practice 
GI 
 gastrointestinal  
GLP 
 good laboratory practices 
HALO 
 hemotoxicity assays via luminescence output 
HERG 
 human ether-a-go-go-related gene 
HER2 
 human epidermal growth factor receptor 2 
HIPAA 
 Health Insurance Portability and Accountability Act 
HIV 
 human immunodeficiency virus 
HNSTD 
 highest non-severely toxic dose 
HPV 
 human papilloma virus 
HR 
 hormone receptor 
IB 
 Investigator’s Brochure 
IC50 
 half maximal inhibitory concentration 
ICF 
 informed consent form 
ICH 
 International Council on Harmonisation 
IHC 
 immunohistochemistry 
IND 
 investigational new drug 
INR 
 international normalized ratio 
IRB 
 institutional review board 
IUD 
 intrauterine device 
IV 
 intravenous 
IWG 
 International Working Group 
LC-MS-MS 
 liquid chromatography with tandem mass spectrometry 
LD 
 longest diameter 
LDH 
 lactate dehydrogenase 
MAD 
 maximum administered dose 
MDM2 
 murine double minute 2  
MDMX 
 murine double minute X 
MED 
 minimum efficacious dose 
MIC-1 
 macrophage inhibitory cytokine-1 
MNC 
 mononuclear blood cells 
MRI 
 magnetic resonance imaging 
MTD 
 maximum tolerated dose 
N 
 sample size 
NCI 
 National Cancer Institute 
NGS 
 Next-Generation Sequencing 
NK 
 Natural Killer 
OATP 
 organic anion transporter polypeptide 
OBD 
 optimal biological dose 
ORR 
 overall response rate 

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OS 
 overall survival 
p21 
 cyclin-dependent kinase inhibitor p21 
p53 
 
 Tumor protein p53, cellular tumor antigen p53, phosphoprotein p53 
 
 
 or tumor suppressor p53 
PARP 
 poly-ADP-ribose polymerase 
PET 
 Positron Emission Tomography 
PD 
 pharmacodynamic 
PFS 
 progression-free survival 
P-gp 
 P-glycoprotein 
PIN 
 prostatic intraepithelial/intraductal neoplasia 
PK  
 pharmacokinetics 
PR 
 partial response 
PT 
 prothrombin time 
PTCL 
 peripheral T-cell lymphoma 
QTc 
 corrected QT interval 
RANO 
 Response Assessment in Neuro-Oncology 
Rb 
 retinoblastoma protein 
RBC 
 red blood cell 
RECIST 
 Response Evaluation Criteria in Solid Tumors 
RNA 
 ribonucleic acid 
RNAseq 
 RNA sequencing 
RT-PCR 
 reverse transcription polymerase chain reaction 
SAE 
 serious adverse event 
SC 
 subcutaneous 
SD 
 stable disease 
SOI 
 start of infusion 
SRC 
 Safety Review Committee 
STD10 
 severely toxic dose in 10% animals 
SULT2A1 
 sulfotransferase family 2A member 1 
t1/2 
 half-life 
TGI 
 tumor growth inhibition 
TLS 
 tumor lysis syndrome 
Tmax 
 time of Cmax 
TP53 
 the gene that encodes p53 
TTR 
 time to respond 
ULN 
 upper limit of normal 
WBC 
 white blood cell 
WT 
 
 
wild-type 

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1 
BACKGROUND AND STUDY RATIONALE 
ALRN-6924 is a synthetic Stapled Peptide designed to disrupt the interaction between the p53 tumor 
suppressor protein and its predominant endogenous inhibitors, MDM2 and MDMX.  For tumors 
expressing WT p53 protein, pharmacological disruption of the interactions between p53 and 
MDM2/MDMX offers a means to restore p53-dependent cell cycle arrest and apoptosis, resulting in 
therapeutic efficacy against human cancers via a novel mechanism.  This clinical trial will investigate the 
safety, tolerability, PK, PD and anti-tumor effects of ALRN-6924 alone or in combination in patients with 
advanced solid tumors and lymphoma with presumed or confirmed WT TP53.  
1.1 
Therapeutic Rationale for Inhibiting MDM2/MDMX to Restore p53 Activity 
The human transcription factor protein p53 induces cell cycle arrest and apoptosis in response to 
deoxyribonucleic acid (DNA) damage and cellular stress, thereby playing a critical role in protecting cells 
from malignant transformation.  Inactivation of p53 by deletion, mutation, or through over-expression of 
its predominant inhibitory proteins MDM2 and MDMX is the single most common defect in human 
cancers.1,2  For tumors with WT TP53, pharmacologic disruption of the interactions between p53 and its 
endogenous suppressors MDM2 and MDMX offers a means to restore p53-dependent cell cycle arrest 
and apoptosis.3,4,5,6 
The ability of MDM2 to negatively regulate p53 function is mediated through several mechanisms, 
including inhibition of p53 transcriptional activity through direct binding, as well as ubiquitination and 
subsequent proteasomal degradation of the p53 protein.6,7 Consequently, aberrant MDM2 over-expression 
and gene amplification results in impaired p53 activity, leading to accelerated cancer development and 
growth.1,8  
MDMX lacks the MDM2-like property to initiate p53 degradation, but possesses a similar p53-binding 
activity that inhibits p53 transcriptional activity.  Amplification of MDMX, which appears to correlate 
with the absence of MDM2 amplification, is observed in many tumor types, including melanoma, breast, 
head and neck, hepatocellular carcinoma, and retinoblastoma.6,9,10  
Because MDM2 and MDMX regulate non-overlapping functions of p53, several lines of evidence suggest 
that selective antagonists targeting only MDM2 have insufficient efficacy, particularly in tumors that 
express high levels of MDMX.6,10,11,12,13 A therapeutic approach targeting both MDM2 and MDMX, 
therefore, is expected to have a higher potential than MDM2-selective molecules to re-activate the p53 
pathway in a greater number of tumor types. 
In addition to enhanced efficacy, a dual inhibitor against both MDM2 and MDMX has an increased 
likelihood of achieving a tolerable efficacious dose without causing severe thrombocytopenia, a frequent 
dose-limiting toxicity (DLT) of MDM2-selective inhibitors in cancer patients.14  For platelet production 
to occur, the p53 pathway must be quiescent, with p53 activity suppressed primarily by MDM2 in the 
bone marrow.15 A potent inhibitor targeting only MDM2 therefore can significantly interfere with 
thrombocytopoiesis before achieving anti-tumor efficacy.  In contrast, a dual MDM2/MDMX therapeutic 
approach, by limiting the over-reliance on MDM2 inhibition, has the potential to fully re-activate the p53 
pathway in tumor cells before causing dose-limiting thrombocytopenia. Restoration of p53 activity with 
inhibition of MDMX rather than MDM2 has been shown to be better tolerated in experiments utilizing 
transgenic and knockout mouse models.16 Enhancement of p53 activity is not expected to result in adverse 

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effects in normal non-hematopoietic organs or tissues, as supported by findings in a genetically 
engineered mouse model.17   
1.2 
Stapled Peptide Technology 
Despite the benefits of a dual-inhibition approach, the identification of small molecule dual antagonists 
with appropriate pharmacological properties has proven challenging, in part due to the structural diversity 
of the p53-binding regions of MDM2 and MDMX.   
One solution lies in converting the α-helical portion of the p53 protein that interacts with MDM2/MDMX 
into a suitably stable, potent and specific therapeutic agent.3,18,19 The resulting molecule would be capable 
of disrupting the interaction between p53 and MDM2/MDMX. Aileron has developed an optimized cross-
linking chemistry to lock, or “staple”, peptides into α-helices that mimic native protein structures.  A 
Stapled Peptide is generated by standard solid-phase peptide synthesis, followed by a selective 
bond-forming reaction that results in an all-hydrocarbon cross-link between two non-contiguous, 
structurally-optimized amino acids.  Because proteases recognize and break down peptides only when 
they are unraveled, the Stapled Peptide technology locks peptides into organized secondary structures and 
confers resistance to proteolysis.  The resulting Stapled Peptide exhibits favorable PK and 
pharmacological properties, including extended plasma half-life and enhanced potency.  A Stapled 
Peptide also retains the molecular target specificity of its underlying native protein structure.  As a result, 
the Stapled Peptide is anticipated to maintain the function of the target protein being mimicked with a low 
likelihood of off-target toxicities.  In select cases, a Stapled Peptide can be designed to penetrate the cell 
membrane, thus permitting modulation of specific intracellular protein-protein interactions.18,20  
1.3 
ALRN-6924 
ALRN-6924 is a Stapled Peptide clinical candidate designed to disrupt the interaction between p53 and 
both MDM2 and MDMX. 
Despite the structural similarity between MDM2 and MDMX, there are important differences in the p53 
binding sites of these proteins that make the development of therapeutic antagonists that can bind to both 
challenging. By mimicking the natural helical peptide fold of p53, the Stapled Peptide ALRN-6924 binds 
equipotently to both MDM2 and MDMX.  Therefore, ALRN-6924 should be less prone to expected 
resistance to MDM2-inhibitor therapy. This resistance may result from compensatory mechanisms, such 
as MDM2 mutation21 and upregulation of MDMX that may result from selective pressure on MDM2 
alone.22  Stapled Peptides like ALRN-6924 have been shown to overcome resistance to MDM2 inhibition 
by these mechanisms in preclinical studies.23,24 
1.4 
Nonclinical Experience with ALRN-6924 
1.4.1 
Pharmacology 
In vitro biochemical assays, x-ray crystallography and ligand displacement studies confirmed the binding 
of ALRN-6924 to target molecules MDM2/MDMX. On-target activation of p53-mediated pathways of 
apoptosis and cell cycle arrest was demonstrated in cancer cells at sub-micromolar concentrations.  As 
expected, the ability of ALRN-6924 to induce cell cycle arrest and apoptotic cell killing was dependent 
on the presence of WT p53 protein. Proliferation and survival of cell lines with WT p53 protein was 
sensitive to ALRN-6924, with IC50 values ranging from 0.2 to 3.3 µM. In SJSA-1 osteosarcoma cells, the 
functional consequences of binding of ALRN-6924 to the p53-regulatory site on MDM2 and MDMX 

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included a concentration-dependent increase in p21 protein, the downstream transcriptional target of p53 
and mediator of cell cycle arrest and cellular senescence; and increases in cellular caspase activity, 
indicative of early apoptotic events.  In contrast, ALRN-6924 had no cytotoxic activity in cells lacking a 
functional p53 signaling pathway.  In RKO-E6 cells, in which p53 expression and signaling is suppressed 
by a stably-transfected human papilloma virus (HPV) E6 oncogene, ALRN-6924 at concentrations 
exceeding 30 µM was not cytotoxic.  ALRN-6924 also did not affect cell viability in SW480 cells, a 
colorectal cancer cell line with mutated p53 that renders the pathway ineffective. With respect to 
hematologic cancers, eleven WT TP53 hematologic cancer cell lines (6 lymphoma and 5 leukemia) were 
evaluated and were highly sensitive to ALRN-6924 intervention as all lines exhibited EC50 less than 
0.6 µM. Taken together, these lines of evidence suggest effectiveness of ALRN-6924 against both solid 
and liquid tumor cell lines across multiple histological origins that retain the p53 WT status. 
The effect of ALRN-6924 on tumor growth was evaluated in murine xenograft models of human tumors, 
including human osteosarcoma, breast cancer and melanoma models.  Statistically significant tumor 
growth inhibition (TGI) was observed in each model following IV dosages, and TGI was found to be 
dose-related in all studies in which a range of dose levels was administered. In particular, ALRN-6924 
exhibited consistent efficacy in mice implanted with WT TP53 human tumors that over-express MDM2 
(e.g., SJSA-1 osteosarcoma xenograft model) or MDMX (e.g., MCF-7 breast cancer xenograft model). 
For example, twice-weekly treatment with ALRN-6924 produced a dose-dependent TGI, with a minimum 
efficacious dose (MED) of 5 mg/kg, in the MCF-7 breast cancer xenograft model (Figure 1). In vivo PD 
assays in this model also demonstrated that ALRN-6924 re-activated the p53 pathway, as shown by 
decreased tumor cell proliferation, increased p53 protein, increased p21 (a downstream transcriptional 
target of p53), and increased apoptosis as indicated by an increase in cleaved poly-ADP-ribose 
polymerase (PARP). 
Figure 1: Effect of ALRN-6924 on Tumor Growth in the MCF-7 Breast Cancer Xenograft Model 
 
 
1.4.2 
Toxicology and Nonclinical Safety 
The pivotal 4-week multiple-dose GLP studies of ALRN-6924 in rats and monkeys utilized twice-weekly 
IV dosing rather than the once-weekly IV dosing planned as the initial clinical regimen. The studies 
provided dose- and exposure-related assessments during both dosing and recovery periods, and results 
0
200
400
600
800
1000
0
6
12
18
24
30
Tumor Volume  ± SEM (mm3)
Days After Treatment Initiation
Vehicle
ALRN-6924 1.25 
mg/kg 2x/week
ALRN-6924 2.5 mg/kg 
2x/week
ALRN-6924 5 mg/kg 
2x/week
ALRN-6924 10 mg/kg 
2x/week
ALRN-6924 20 mg/kg 
2x/week

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were utilized to define the maximum tolerated doses (MTD) and estimate the severely toxic dose for 10% 
(STD10) of rats and the highest non-severely toxic dose (HNSTD) in monkeys.  All gross and microscopic 
signs of intolerance (e.g., reduced organ weights, sporadic findings of multi-tissue hemorrhage and 
hepatic necrosis) and changes in serum chemistry parameters were considered as secondary to red blood 
cell (RBC), platelet and/or white blood cell (WBC) depletions or anorexia and dehydration in both 
species. Recovery assessments revealed regenerative and compensatory changes consistent with marrow 
cell survival and reversibility of all related hematologic and secondary toxicities.   
The DLT in both animal species appears to be related to the suppression of hematopoietic cells in the 
bone marrow, in particular cells of the megakaryocyte lineage, resulting in significant decreases in 
peripheral blood platelets that demonstrated recovery upon the cessation of dosing (see Figure 2). 
Figure 2: Dose-dependent Platelet Response in 4-week Monkey GLP Toxicity Study 
 
Female results shown as representative data 
 
The STD10 in rats was defined at 10 mg/kg based on the mortality of one animal in a satellite group for 
hematology sampling during recovery. The HNSTD in monkeys was defined at 5 mg/kg, based on a 
complete lack of significant thrombocytopenia at this lowest dose level. However, almost all of the 
monkeys at the mid- and high-dose levels tolerated ALRN-6924 administration well; only one animal at 
each of these dose levels developed significant thrombocytopenia (<100,000 x 106/ml). 
Rats are more sensitive to the bone marrow and hematologic effects of ALRN-6924 than monkeys on the 
basis of exposures at maximally tolerated doses. Exposure at rat STD10 (AUC0-∞=562 µg•hr/mL at 
10 mg/kg) was below that of HNSTD in monkeys (AUC0-∞=813 µg•hr/mL at 5 mg/kg). These in vivo 
results correlate with those obtained from in vitro hemotoxicity assays via luminescence output (HALO). 
In these investigations, ALRN-6924 in general inhibited the induced proliferation of bone marrow 
precursor cells from rats to a greater extent than those from monkeys or humans. IC50 values were ~2- to 
8-fold higher for rat cells than for monkey or human cells, with the largest difference noted for 
megakaryocyte colony forming cells, the platelet precursors.  These results correlate with in vivo findings 
indicating that rats are more sensitive to the bone marrow and hematologic effects of ALRN-6924 than 
monkeys on the basis of dose and exposures at maximally tolerated doses.  These results also suggest that, 
in terms of projecting potential bone marrow and hematological toxicity levels in humans, the monkey 
PK-PD data may be more clinically relevant than the rat data. 

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ALRN-6924 was negative in genetic toxicology studies, including bacterial mutagenicity (Ames), 
chromosomal aberrations (human peripheral blood lymphocyte) and in vivo micronucleus (rat bone 
marrow) assays.  Safety pharmacology studies were performed to assess the effects of ALRN-6924 on 
hERG potassium channels in vitro and on cardiac function in cynomolgus monkeys. There were no 
significant adverse findings in these studies. 
Compared to the twice-weekly IV dosing schedule utilized in the 4-week GLP toxicity studies, the first-
in-human clinical trial of ALRN-6924 will initially assess once-weekly IV dosing for three weeks.  In 
addition, the demonstrated reversibility of ALRN-6924-induced hematologic effects, the ability to detect 
such findings with routine laboratory measurements, and the availability of effective supportive therapies, 
all provide additional safety margin in the clinic.   
1.4.3 
Pharmacokinetics and Absorption, Distribution, Metabolism and Excretion 
Pharmacokinetic studies (Table 1) characterize exposure kinetics following single IV administrations of 
ALRN-6924 in mice, rats and monkeys, including evaluations of two different dosing formulations in rats 
and monkeys. Using qualified liquid chromatography with tandem mass spectrometry (LC-MS-MS) 
methods for efficacy models and dose range-finding (DRF) studies, and validated methods for GLP safety 
studies, exposure was characterized in mice at the MED in efficacy models and in rats and monkeys at 
tolerated and non-tolerated doses in toxicology studies. Exposures generally increased proportionally with 
dose, although an apparent plateau was observed at the highest dose of the 4-week monkey toxicology 
study. No sex-based differences were observed in either species, and no accumulation was observed 
following multiple doses.  
Table 1: 
Pharmacokinetic Studies Completed with ALRN-6924 
Study Type 
Description 
Analytical Methods 
Development and  
Validation 
Rat plasma 
Monkey plasma 
Human plasma 
In vitro dosing solutions 
In vivo dosing solutions 
Stability in rat whole blood 
Stability in monkey whole blood 
Method transfer report 
Absorption/Kinetics 
Single-dose mouse 
Single-dose rat 
Multi-dose rat 
Single-dose rat (2 formulations) 
Single-dose monkey (2 formulations) 
Distribution 
Plasma protein binding 
Conc.-dependent protein binding 
Substrate for hepatobiliary transporters 
Metabolism 
Multi-species hepatocytes 
Rat and monkey in vivo 
Excretion 
Rat bile and urine  
PK Drug 
Interactions 
CYP enzyme inhibition 
CYP enzyme induction 
Hepatic transporter inhibition 
 

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The in vitro protein binding of ALRN-6924 was evaluated over a range of concentrations in mouse, rat 
and monkey plasma, as well as human plasma samples from normal subjects and hypoalbuminemic 
patients.  Protein binding ranged from 92% to 98% in plasma of mice, rats, dogs, monkeys, and humans 
following incubation of ALRN-6924 at a single concentration of 2 µM, and exceeded 98% in mouse and 
rat plasma up 250 µM. In human and monkey plasma, free ALRN-6924 fractions of 3-4% were measured 
at ALRN-6924 concentrations up to 150 µM, corresponding to expected Cmax values from clinical doses 
up to 15 mg/kg, rising to 12-14% at concentrations >200 µM. In plasma from hypoalbuminemic patients, 
a similar rise was seen at >100 µM concentrations of ALRN-6924, corresponding to expected Cmax values 
from clinical doses up to 10 mg/kg. The concentration-dependent plasma protein binding provides a 
possible explanation for the apparent plateau in exposure observed at the high-dose group (20 mg/kg) in 
the 4-week monkey GLP toxicity study, and suggests less-than-dose-proportional exposure may be seen 
at very high clinical doses, in particular for patients with hypoalbuminemia. 
In vitro studies demonstrated a similar metabolite profile across species, including humans, providing 
support for the rat and the monkey as suitable species for toxicology studies. Proteolysis is the major 
biotransformation pathway of ALRN-6924. The predominant metabolite, ALRN-8714, is a 3-amino acid 
truncation with the cyclic peptide portion intact, and the same metabolite profile was noted in in vitro 
stability studies with mouse, rat, monkey, and human cryopreserved hepatocytes. In a single-dose rat 
study, hepatobiliary metabolism and elimination represented the predominant clearance pathway for 
ALRN-6924, with ALRN-8714 being the major excretion product observed in the bile.  ALRN-8714 was 
also observed in the plasma in both the rat and monkey 4-week GLP toxicology studies, with adequate 
exposures in these studies to provide characterization of its impact on the overall safety profile of ALRN-
6924. In the monkey, ALRN-8714 plasma exposure was 10% of the ALRN-6924 AUC, and in the rat, 
ALRN-8714 exposure was 6% of the ALRN-6924 AUC. Accumulation of ALRN-8714 was not observed 
with repeated twice-weekly dosing in rats or monkeys.   
Inhibition or induction of cytochrome P450 (CYP) enzymes by ALRN-6924 appears to be negligible at 
clinically-relevant concentrations, although interactions may occur at high exposures of ALRN-6924 with 
drugs that are predominantly cleared by hepatobiliary transporters (please refer to Appendix B of this 
protocol or the Investigator’s Brochure for additional information). 
1.4.4 
ALRN-6924 Administered in Combination with Palbociclib 
1.4.4.1 Pharmacology 
Because p53 plays a central role in a variety of signal transduction pathways, including cell cycle, 
senescence and apoptosis, that are critical to the treatment of cancer, reactivation of p53 by ALRN-6924 
can play an important role in combination therapy to provide a greater anti-tumor response than single-
agent treatment and minimize resistance to individual drugs.   
CDK4/6 inhibitors induce apoptosis, senescence, and cell growth arrest via the retinoblastoma protein 
(Rb) pathway, which converges on the p53 pathway through interrelated mechanisms as shown in 
Figure 3. Co-amplification of MDM2 and cyclin-dependent kinase 4 (CDK4) (both located on 
chromosome 12q13 within 11 mega base-pairs only) are oncogenic events, suggesting that combinations 
of MDM2-inhibitors such as ALRN-6924 and CDK4/6inhibitors such as palbociclib may be synergistic 
(Figure 4). 

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Figure 3: Combined Mechanism of Action of ALRN-6924 and Palbociclib 
 
The p53 and Rb pathways converge to trigger apoptosis, senescence, and cell growth arrest (Adapted from Lønning 
and Knappskog, “Mapping genetic alterations causing chemoresistance in cancer: Identifying the roads by tracking 
the drivers” Oncogene. 2013 Nov 14;32(46):5315-30)25 

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Figure 4: Co-amplification of MDM2 and CDK4 
 
The p53 and Rb pathways are often disabled by MDM2 or CDK4 gene amplification; both genes reside on 
Chromosome 12 (Adapted from B.A. Van Tine, “Multiple Molecular Subtypes of Sarcoma Allow for Orphan Drug 
Development,” The Journal of Targeted Therapies in Cancer 2016)26 
The anticancer activity of the CDK4/6 inhibitor palbociclib was enhanced by combining with ALRN-
6924 in an in vitro study. As shown in Figure 5 (left panel), treatment of SJSA1 osteosarcoma cancer 
cells for 120 hour with ALRN-6924 alone inhibited cellular proliferation with an IC50 value of 0.04 µM 
and treatment with palbociclib alone yielded an IC50 of 0.06 µM. However, treatment with increasing 
concentrations of ALRN-6924 combined with palbociclib in a 1:1 ratio resulted in an improved IC50 of 
0.02 µM, suggesting additive to synergistic complementarity of the two anticancer agents when dosed 
together in this MDM2/CDK4-co-amplified cell line. As shown in the right panel of Figure 5, the 
combination treatment was also effective against SJSA1 cancer cells when ALRN-6924 was administered 
first, followed by washout and subsequent treatment with palbociclib. This result suggests that the 
sustained anti-proliferative effects of ALRN-6924 are enhanced by palbociclib. 

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Figure 5: Effect of ALRN-6924 ± Palbociclib on In Vitro Proliferation of MDM2/CDK4-co-
amplified SJSA1 Osteosarcoma Cancer Cells 
 
Left panel: Effect of ALRN-6924 ± palbociclib on in vitro proliferation of SJSA1 osteosarcoma cancer cells when 
dosed simultaneously for 120 hours. Right panel: Effect when SJSA1 cells are dosed with ALRN-6924 for 24 hours, 
washed, then dosed with palbociclib for a further 96 hours. 
 
The mechanism underlying the enhancement of ALRN-6924’s anti-proliferative effects when combined 
with palbociclib was investigated by measuring cell cycle arrest, apoptosis, and the up- and down-
regulation of specific molecular markers in cancer cells in vitro following single-agent or combination 
treatment. As shown in Figure 6 (top panel), caspase activation (a measure of apoptosis induction) was 
evident when both agents were dosed simultaneously in SJSA1 cancer cells. 5’-bromo-2’deoxyuridine 
(BrdU) incorporation into the DNA of SJSA1 cells was measured to evaluate cell cycle arrest (center 
panel), with results showing a decrease in cycling cells when treated with the combination. Western blot 
analysis of phosphorylated Rb, Forkhead box protein M1 (FOXM1), p53, and p21 (bottom panel) all 
support the conclusion that palbociclib and ALRN-6924 enhance the activity of one another by on-
mechanism cell cycle arrest and cancer cell killing in this MDM2/CDK4-co-amplified cell line. 

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Figure 6: Mechanism of Enhancement of Anti-proliferative Effects of ALRN-6924 when 
Combined with Palbociclib 
 
 
 
Abbreviations: A = ALRN-6924; BrdU = 5’-bromo-2’-deoxyuridine; FOXM1 = Forkhead box protein M1;  
hr(s) = hour(s); p = palbociclib; p21/53 = Tumor protein 21/53; Rb = retinoblastoma protein; veh = vehicle 
Top panel: caspase activation (a measure of apoptosis induction) in SJSA1 cells. Center panel: BrdU incorporation 
(a measure of cell cycle arrest) in SJSA1 cells. Bottom panel: Western blot analysis of phosphorylated Rb, FOXM1, 
p53, and p21 in SJSA1 cells following treatment with ALRN-6924 (A), palbociclib (P), or the combination (A+P). 
 

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The combination of ALRN-6924 and palbociclib was also tested in MCF-7 and SJSA1 mouse xenograft 
models. SJSA1 harbors DNA amplification of both MDM2 and CDK4 genes, which neighbor one another 
on chromosome 12q, while MCF-7 harbors a deletion of the CDKN2A gene, the product of which is a 
natural inhibitor of MDM2 and CDK4. In these studies, athymic nu/nu mice were xenotransplanted with 
MCF-7 or SJSA1 cells and then treated with either vehicle, ALRN-6924 alone once-weekly for 21 days, 
palbociclib alone once daily for 21 days, or a combination of the two agents with ALRN-6924 dosed 
either 6 hours before or 6 hours after palbociclib on days when both were dosed together. As shown in 
Figure 7, at the doses administered in this study, the combination of ALRN-6924 and palbociclib yielded 
11-31% greater tumor growth inhibition and 17-50% longer time-to-progression than either single agent 
alone, with administration of ALRN-6924 before palbociclib providing better efficacy in both models. 
Figure 7: Effect of Combination of ALRN-6924 and Palbociclib on Tumor Growth in MCF-7 and 
SJSA1 Mouse Xenograft Models 
 
(continued on next page) 

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Top panel: MCF-7 mouse xenograft model. Bottom panel: SJSA1 mouse xenograft model. 
Abbreviations: d22 = Day 22; SEM = standard error of the mean; TGI = tumor growth inhibition 
 
1.4.4.2 Pharmacokinetics 
No PK interaction is anticipated between ALRN-6924 and palbociclib. The two drugs are metabolized 
and eliminated by independent mechanisms; namely, proteolytic metabolism with hepatic uptake and 
biliary excretion for ALRN-6924, while palbociclib is primarily metabolized by CYP3A and 
sulfotransferase family 2A member 1 (SULT2A1) with the major metabolite in feces as the sulfamic acid 
conjugate. It is advised to avoid concomitant use of strong CYP3A inhibitors, and moderate and strong 
CYP3A inducers while on palbociclib therapy. Doses of sensitive CYP3A substrates with a narrow 
therapeutic index may need to be reduced, as palbociclib may increase their exposures. Palbociclib, at 
clinically relevant concentrations has a low potential to inhibit transporters P-glycoprotein (P-gp), breast 
cancer resistance protein (BCRP), OAT1, OAT3, OCT2, OATP1B1 and OATP1B3, and its oral 
absorption is unlikely to be affected by P-gp and BCRP mediated transport. 
Studies with ALRN-6924 indicate a low likelihood of induction or inhibition of CYP enzymes, 
suggesting any metabolism-based drug-drug interactions between ALRN-6924 and palbociclib are 
unlikely. Though studies show that ALRN-6924 is an inhibitor of OATP1B1 and OATP1B3 transporters, 
palbociclib is not known to be a substrate of these transporters, and no hepatobiliary pharmacokinetic 
drug-drug interactions have been reported for palbociclib. 27 
ALRN-6924 and palbociclib are administered by intravenous and oral routes, respectively, and there will 
be minimum interaction at the gut level. It is recommended to administer palbociclib with food. Under fed 
conditions there are no clinically relevant effects of proton pump inhibitors, H2-receptor antagonists, or 
local antacids on palbociclib exposure. 

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In nu/nu mice (non-tumor-bearing), the PK of ALRN-6924 was not affected by palbociclib (and vice 
versa) as shown in Figure 8 and Table 2.   
Figure 8: Plasma Concentrations of ALRN-6924 and Palbociclib when Administered Alone or in 
Combination in Nu/nu Mice 
 
 
Table 2: 
Pharmacokinetic Parameters of ALRN-6924 and Palbociclib when Administered Alone 
or in Combination in Nu/nu Mice 
Alone 
Co-administered 
 
Cmax 
µg/mL 
AUClast  
µg·hr/mL 
Cmax  
µg/mL 
AUClast  
µg·hr/mL 
ALRN-6924 
138 
686 
156 
759 
Palbociclib 
2.9 
37 
2.6 
29 
 
1.5 
Clinical Experience with ALRN-6924  
There was no clinical experience with ALRN-6924 prior to initiation of this Phase 1/2a study. As of 
26 February 2018, a total of 118 patients had received treatment either in the present study or in 
Study ALRN-6924-1-02, which is an ongoing Phase 1/1b study of ALRN-6924 in patients with acute 
myeloid leukemia or advanced myelodysplastic syndrome.   
1.6 
Clinical Experience with Palbociclib 
Palbociclib (IBRANCE®) is an inhibitor of CDK4 and CDK6.  
Palbociclib has been approved by the FDA for the treatment of hormone receptor (HR)-positive, human 
epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination 
with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or fulvestrant in 
women with disease progression following endocrine therapy. 

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2 
STUDY OBJECTIVES 
2.1 
Phase 1 Dose Escalation (ALRN-6924 administered as single agent therapy) 
2.1.1 
Primary Objectives 
• 
Evaluate the safety and tolerability of ALRN-6924 in adult patients with advanced solid 
tumors or lymphomas with WT TP53 who are refractory to or intolerant of standard therapy, 
or for whom no standard therapy exists 
• 
Determine the DLTs, the MTD or OBD of ALRN-6924 in adult patients with advanced solid 
tumors or lymphomas 
2.1.2 
Secondary Objectives 
• 
Describe the PK of ALRN-6924 and its metabolites in blood following single and multiple IV 
infusions. 
• 
Assess potential patient biomarkers (e.g., p53 status, MDM2 and MDMX expression levels), 
the effect of ALRN-6924 treatment on these biomarkers, and possible correlation between 
these biomarkers and clinical response. 
• 
Assess the effect of ALRN-6924 treatment on potential PD biomarkers in tumor biopsy 
samples including bone marrow aspirates (e.g., p21, caspase, MDM2) and blood samples 
(e.g., MIC-1), and assess possible correlation between these biomarkers and clinical response.  
• 
Evaluate potential clinical activity of ALRN-6924. 
• 
Investigate the immunogenicity of ALRN-6924. 
2.1.3 
Exploratory Objectives 
• 
Starting at dose level 3:  Assess the effect of ALRN-6924 treatment on potential PD 
biomarkers (e.g., p21, p53, caspase) in circulating tumor cells (CTC), where detectable, or in 
mononuclear blood cells (MNC). 
• 
Assess the effects of ALRN-6924 treatment on cell-free DNA from blood. 
2.2 
Phase 2a Dose Expansion (ALRN-6924 administered as single agent therapy) 
2.2.1 
Primary Objectives 
• 
Assess overall response rate (ORR) 
• 
Further evaluate the safety and tolerability of ALRN-6924  
2.2.2 
Secondary Objectives 
• 
Describe the PK of ALRN-6924 and its metabolites in blood following single and multiple IV 
infusions in patient populations selected for dose expansion with single agent therapy 
• 
Assess duration of response (DOR) 
• 
Assess progression-free survival (PFS) 
• 
Assess overall survival (OS) 

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• 
Assess PFS and OS at 1 year 
• 
Assess time to response (TTR) 
• 
Assess the effect of ALRN-6924 treatment on potential pharmacodynamic (PD) biomarkers 
in tumor biopsy samples (including bone marrow aspirates, where clinically indicated) by 
measuring potential biomarkers such as p53, p21, caspase, MDM2, MDMX and in blood 
samples by measuring potential biomarkers such as macrophage inhibitory cytokine-1 [MIC-
1] and assessing possible correlation between these biomarkers and clinical outcomes   
• 
Investigate the immunogenicity of ALRN-6924 
2.2.3 
Exploratory Objectives 
• 
Assess the effects of ALRN-6924 treatment on cell-free DNA from blood. 
• 
Assess the effect of ALRN-6924 treatment on potential PD biomarkers (e.g., p21, p53, 
caspase) in circulating tumor cells (CTC), where detectable, or in mononuclear blood cells 
(MNC). 
• 
Assess the effect of ALRN-6924 using alternative response criteria other than the IWG 2014 
or RECIST 1.1 criteria  
2.3 
Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 Co-amplified Solid Tumors 
(ALRN-6924 plus palbociclib) 
2.3.1 
Primary Objectives 
• 
Assess ORR 
• 
Evaluate the safety and tolerability of ALRN-6924 and palbociclib when administered in 
combination 
2.3.2 
Secondary Objectives 
• 
Describe the PK of ALRN-6924 (and its metabolites) and palbociclib when administered in 
combination 
• 
Estimate DOR 
• 
Estimate additional measures of efficacy, including TTR, PFS, OS, and PFS and OS at 1 year 
2.3.3 
Exploratory Objective 
• 
Explore potential markers of response to treatment with ALRN-6924 and palbociclib 

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3 
INVESTIGATIONAL PLAN 
3.1 
Study Rationale 
ALRN-6924 has demonstrated single-agent anti-tumor activity in multiple animal models of human 
tumors.  These observations, coupled with the documented nonclinical safety profile of ALRN-6924, 
support the clinical investigation of ALRN-6924 in a variety of human cancer types.   
The results of in vitro and in vivo studies indicate enhanced anti-tumor effects when ALRN-6924 and 
palbociclib are administered in combination. A Phase 2a expansion cohort will be enrolled to evaluate the 
combination of ALRN-6924 and palbociclib in patients with MDM2 amplified or MDM2/CDK4 co-
amplified solid tumors including, but not limited to, sarcomas, glioblastomas, carcinomas of the breast, 
and non-small cell lung cancer. The inclusion of patients with glioblastomas is based on non-clinical 
studies conducted with a similar stapled peptide, ATSP-7041, that evaluated the distribution of this agent 
in the context of an intact blood-brain barrier.28 This work demonstrated exposure of the radiolabeled 
stapled peptide in central nervous system (CNS) tissue in non-tumor-bearing rats, with a 1% brain:plasma 
ratio for peak concentration and a 1.7% brain:plasma ratio for AUC. In the context of a CNS tumor with 
disrupted blood-brain barrier, CNS tumor penetration is expected to be substantially higher, as is known 
for bevacizumab (Avastin®), a high molecular weight monoclonal antibody that is not believed to cross an 
intact blood-brain barrier, yet is FDA-approved for treatment of primary and metastatic brain tumors.29 
The selection of patients with MDM2-amplified or MDM2/CDK4 co-amplified solid tumors is intended 
to identify patients who may be more likely to respond to the ALRN-6924 and palbociclib combination 
regimen, as the products of these amplifications are the targets of the respective agents. 
3.2 
Study Overview 
This is a Phase 1/2a open-label, multi-center, dose-escalation and dose expansion study designed to 
evaluate the safety, tolerability, PK, PD, and anti-tumor effects of ALRN-6924 administered by IV 
infusion once weekly for 3 consecutive weeks on Days 1, 8, and 15 of a 28-day cycle (Dose Regimen A 
or DR-A and DR-A-2), twice weekly for 2 consecutive weeks on Days 1, 4, 8, and 11 of a 21-day cycle 
(Dose Regimen B or DR-B), or three times weekly for one week on Days 1, 3, and 5 of a 21-day cycle 
(Dose Regimen C or DR-C) in patients with advanced solid tumors or lymphomas that are anticipated to 
express WT TP53.   
This study consists of a Phase 1 Dose Escalation Phase (DEP) and a Phase 2a Dose Expansion Phase 
(EXP).  The DEP is a “3+3” dose escalation design to establish the MTD or the OBD of ALRN-6924. 
The EXP will enroll up to 5 distinct groups of patients with specific solid tumors and/or lymphomas to 
further investigate the clinical safety profile and potential efficacy of ALRN-6924 at the MTD, OBD, or 
an alternative dosing regimen.  
Peripheral T-cell lymphoma (PTCL) has been selected as one of the Phase 2a EXP groups to be further 
studied; up to 3 cohorts in PTCL may be studied in order to determine the optimal dosing regimen.  
Another Phase 2a EXP group will include patients with MDM2 amplified or MDM2/CDK4 co-amplified 
solid tumors who will receive ALRN-6924 in combination with palbociclib.  As these agents have not 
previously been co-administered, a safety run-in of 6-8 safety evaluable patients will first be enrolled to 
determine the optimal dosing regimen for the combination. 

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Treatment of patients in the dose escalation and the dose expansion phases of the study 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 receiving clinical benefit may continue on study after a discussion between 
the Principle Investigator and Medical Monitor. 
Starting at Dose Level 4 (DEP), patients with a Human Papilloma Virus (HPV)-positive malignancy will 
be excluded from enrollment.  This is owing to the fact that HPV-infected tumor cells continue to express 
the viral E6 protein, which is known to cause degradation of p53, hence rendering the expected ALRN-
6924-mediated dual inhibition of MDM2/MDMX very unlikely to restore p53 function.  
Phase 1 – Dose Escalation (ALRN-6924 administered as single agent therapy) 
In DEP, patients may meet the TP53 WT requirement through one of the following scenarios (per the 
exception to exclusion criterion 1, patients previously treated with an MDM2-inhibitor are also eligible, 
provided that a biopsy taken after completion of the last treatment with an MDM2-inhibitor meets one of 
the following): 
• 
Patients may be eligible based on a fresh biopsy or archived tissue that is ≤1 year old. All samples 
will be tested for TP53 status using Next-Generation Sequencing (NGS) at the central laboratory. The 
central laboratory will determine the TP53 status as expeditiously as possible.   
• 
Upon approval from the medical monitor, patients may also enroll and initiate study treatment based 
on wildtype TP53 status that was determined by another laboratory.  Again, this testing must have 
been performed on tumor samples obtained no more than one year ago. These archived specimens 
with previously determined TP53 status must still be submitted for NGS testing at the central 
laboratory; the central laboratory’s result will determine the patient’s official classification as either 
TP53 wildtype or TP53 mutant. 
Patients who do not have archived tissue, and for whom a biopsy poses a significant risk, cannot be 
enrolled. 
In DEP, patients who satisfy all inclusion and exclusion criteria will be enrolled in cohorts of 3 to 6 
patients to receive ALRN-6924.  ALRN-6924 will be administered by IV infusion in Dose Regimen A 
over 1 hour (±15 min) on Days 1, 8 and 15 of a 28-day cycle, over 2 hours (±15 min) on Days 1, 8 and 15 
of a 28-day cycle in Dose Regimen A-2 starting at Dose Level 7, or in Dose Regimen B over 1 hour (±15 
min), starting at Dose Level 3, on Days 1, 4, 8, and 11 of a 21-day cycle. Patients who remain on study 
treatment for 2 years or longer may have their dosing frequency reduced, at the discretion of the 
investigator (i.e., Days 1 and 15 of a 28-day cycle (DR-A) or Days 1 and 8 of a 21-day cycle (DR-B).  In 
the event that disease control is not maintained, the original dosing schedule may be resumed.   
After the MTD or OBD is established for a particular dosing regimen, additional patients may be enrolled 
in up to 5 expansion cohorts (approximately 20 patients per expansion cohort) to gain further experience 
in particular patient or tumor types or to test alternative dosing regimens. Selection of patient or tumor 
types will be determined in part on the basis of observations made in the dose escalation portion of the 
study. 

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Phase 2a – Dose Expansion in PTCL (ALRN-6924 administered as single agent therapy) 
Patients may meet the TP53 requirement through one of the following scenarios: 
• 
Patients need to be tested for TP53 status, using a fresh biopsy or archived tissue that is ≤1 year 
old.  All samples will be tested for TP53 status using NGS at the central laboratory. The central 
laboratory will determine the TP53 status as expeditiously as possible.  Investigators are 
encouraged to await the TP53 test result, however, if this is clinically deemed not to be in the 
patient’s best interest, enrollment and the initiation of study treatment may proceed, prior to the 
central laboratory result becoming available. Central laboratory testing is still required to confirm 
WT p53 status.    
• 
Upon approval from the medical monitor, patients may also enroll and initiate study treatment 
based on wildtype TP53 status that was determined by another laboratory.  This testing must have 
been performed on tumor samples obtained no more than one year ago and the patient must not 
have received systemic cytotoxic therapy in the interval since the tissue was obtained. These 
archived specimens with previously determined TP53 status must still be submitted for NGS 
testing at the central laboratory; the central laboratory’s result will determine the patient’s official 
classification as either TP53 wildtype or TP53 mutant. 
Patients who do not have archived tissue, and for whom a biopsy poses a significant risk, cannot be 
enrolled. 
ALRN-6924 will be administered by IV infusion in Dose Regimen A over 1 hour (±15 min) on Days 1, 8 
and 15 of a 28-day cycle, in Dose Regimen B over 1 hour (±15 min) on Days 1, 4, 8, and 11 of a 21-day 
cycle, and in Dose Regimen C over 1 hour (±15 min) on Days 1, 3, and 5 of a 21-day cycle.  For the Dose 
Regimen C cohort, 6-8 patients will be enrolled in a safety run-in part and the treating investigators, along 
with the Medical Monitor, will review safety and tolerability through Cycle 1 prior to opening the full 
DR-C expansion cohort.  
Phase 2a – Dose Expansion in MDM2 Amplified or MDM2/CDK4 Co-amplified Solid Tumors 
(ALRN-6924 plus palbociclib) 
Patients enrolled in this cohort must have MDM2 amplified or MDM2/CDK4 co-amplified solid tumors, 
as determined by local, commercial or central assays such as NGS, fluorescent in situ hybridization 
(FISH) or comparative genomic hybridization (CGH). However, all patients must have fresh or archival 
tissue submitted to the central laboratory for NGS testing. The central laboratory’s results will determine 
the patient’s official classification as MDM2 amplified, MDM2/CDK4 co-amplified, or neither MDM2 
amplified nor MDM2/CDK4 co-amplified. 
Mutational analysis of TP53 is not required for this cohort, as TP53 mutations are extremely rare among 
patients with MDM2 amplifications. However, patients with known mutations or deletions of TP53 will 
be excluded from study participation. Likewise, patients with known Rb mutations will be excluded, as 
the cell cycle arrest and senescence response by palbociclib’s CDK4/6 inhibition is mediated by Rb, and 
loss or functional mutation of Rb is specifically associated with resistance to palbociclib.30 
Enrollment of the first 3 patients in this cohort will be separated in time by at least one week each, to 
assess for unexpected acute toxicities related to administration of the treatment regimen. ALRN-6924 will 
be administered by IV infusion over 1 hour (±15 min) on Days 1, 8, and 15 of a 28-day cycle. Palbociclib 

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will be administered at an oral dose of 100 mg daily for 21 days (one dose level below the approved oral 
dose of 125 mg) in the same 28-day cycle. A safety run-in group of 6-8 patients will first be enrolled and 
evaluated before further patients are permitted to enroll. In the event that this regimen is not determined to 
be safe or tolerable at these dose levels, the dose of ALRN-6924 will be decreased by 25% and/or the 
dose of palbociclib will be decreased by one dose level (to 75 mg/day), as needed based on the pattern of 
toxicities encountered. An additional 6-8 patients will be assessed in a safety run-in using the reduced 
dose level before further enrollment is permitted. One subsequent reduction of the ALRN-6924 dose by 
25% may be implemented, if safety and tolerability are still not acceptable. Once the safety run-in is 
complete, all subsequent patients will be enrolled at the recommended dose level. 
Phase 1 and Phase 2a 
Safety will be evaluated based on the incidence, severity, duration, causality, seriousness, and type of AE, 
and changes in the patient’s physical examination, vital signs and clinical laboratory results.  Investigators 
will use the NCI CTCAE version 4.03 to assess the severity of AEs.  The immunogenicity of ALRN-6924 
will be assessed by the measurement of anti-ALRN-6924 antibodies. 
If the safety profile appears favorable, the study may be amended in the future to expand existing cohorts 
or subsets of existing cohorts, add cohorts to test additional cancer types or add cohorts to test other 
combination treatments with ALRN-6924. 
3.2.1 
Pharmacokinetic, Pharmacodynamic, and Clinical Activity Assessments 
Blood samples will be collected after single and multiple infusions for PK analysis of ALRN-6924 and its 
metabolites to correlate clinical responses with exposure levels and assess inter-individual variability.  
Patients receiving ALRN-6924 in combination with palbociclib will also have additional blood samples 
collected for determination of PK parameters for palbociclib. 
Levels of p53 and its endogenous inhibitors MDM2 and MDMX may be assessed before and after 
exposure to ALRN-6924, and the possible correlation between these biomarkers and outcome or response 
will be investigated.  In the cohort of patients with MDM2 amplified or MDM2/CDK4 co-amplified solid 
tumors, the correlation of response with MDM2, MDMX, and/or CDK4 gene copy number and other 
genetic and protein biomarkers will be investigated. 
Pharmacodynamics (PD) may be assessed by laboratory-based evaluation of several biomarkers of p53 
activation, including levels of p21, caspase and MDM2 in tumor tissue, and where available in CTC, or 
MNC, as well as MIC-1 in blood, before and after treatment with ALRN-6924. Pharmacodynamic effects 
on the composition of cell-free DNA from blood may be evaluated. 
Results available from previous genetic and biomarker tests, and additional tests of the blood and tumor 
samples for biomarkers relevant to the safety and efficacy of ALRN-6924 (or ALRN-6924 plus 
palbociclib) may be investigated for possible correlation with patient outcomes.  Any remaining samples 
collected for PK, biomarker assays, and immunogenicity may be used for exploratory biomarker 
profiling, sample identification, or additional safety assessments (e.g., anti-drug antibody 
characterization) as appropriate. 
For any cohort that includes adolescents, an assessment of pharmacologic differences between 
adolescents and adults will be performed. 

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Phase 1 – Dose Escalation  
Clinical Activity: 
Clinical activity or response will be evaluated by standard imaging assessments, such as computed 
tomography (CT), magnetic resonance imaging (MRI), and bone scans.  In addition, [18F]-
fluorodeoxyglucose positron emission tomography (FDG-PET) or other techniques considered clinically 
appropriate for the patient’s specific disease type can be used. Anti-tumor activity will be assessed using 
RECIST 1.1 (Appendix K) for patients with solid tumors or using IWG (2014) criteria (Appendix L) for 
patients with lymphomas.  The same imaging technique should be used at each assessment for a patient.  
Positron Emission Tomography (PET) Scans: 
• 
For patients with an FDG-avid lymphoma, FDG-PET imaging will be performed at baseline 
and post-baseline as outlined in IWG 2014 during DEP and in the EXP.   
• 
For solid tumor patients, FDG-PET imaging may be performed at baseline and subsequently 
post-dose at the first occurrence of stable disease in applicable patients as an adjunct to 
determine anti-tumor activity, as outlined in RECIST 1.1. (Applicable patients are those who 
had an evaluable FDG-PET-scan performed prior to starting treatment with study drug.) 
NOTE:  PET/CT scans may substitute for contrast-enhanced CT scans provided the CT performed as part 
of a PET–CT is of similar diagnostic quality as a diagnostic CT with IV and oral contrast. As with CT-
imaging, the same imaging technique should be used for each patient’s PET assessment. 
Phase 2a – Dose Expansion  
Biopsies: 
In the Phase 2a EXP PTCL cohorts, optional biopsies will be taken for PD and p53 status determination 
purposes: one during screening, one during treatment, and one or more at times of suspected and/or 
confirmed progression.  In the palbociclib combination cohort, if a biopsy is taken for any reason during 
the study, the samples may be used for further analysis.  Samples might be submitted for whole exome 
sequencing (with a paired germline sample) and RNA sequencing (RNAseq), and results will be 
compared between pre-treatment and on-treatment, and time of suspected and/or confirmed progression 
tumor samples for markers of disease response and resistance. Protein expression via 
immunohistochemistry and RNA expression via quantitative RT-PCR will be examined on specimens 
obtained prior to beginning treatment, during treatment with ALRN-6924, and then upon suspected and/or 
confirmed progression.  Biopsy details may be found in the Laboratory Manual.   
Clinical Activity: 
Clinical activity or response will be evaluated by standard imaging assessments, such as computed 
tomography (CT) and FDG-PET or other techniques considered clinically appropriate for the patient’s 
specific disease type.  Anti-tumor activity will be assessed using RECIST 1.1 (Appendix K) for patients 
with solid tumors, ResponseAssessment in Neuro-Oncology (RANO) for glioblastoma (Appendix M), or 
IWG (2014) criteria (Appendix L) for patients with lymphomas.  The application of additional assessment 
techniques may also be considered, as appropriate, throughout the conduct of the study.  For patients 
enrolled to the Phase 2a expansion cohort of patients with MDM2 amplified or MDM2/CDK4 co-
amplified solid tumors, this will include response criteria that are used to assess anticancer agents that 

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elicit an immune response, such as iRECIST (see Appendix N)31 This is owing to the fact that p53-
activation has numerous effects on the immune system.32 The same evaluation technique(s) should be 
used at each assessment for a patient.  
For patients with an FDG-avid lymphoma, FDG-PET imaging will be performed at baseline and post-
baseline as outlined in IWG 2014.   
NOTE: PET/CT scans may substitute for contrast-enhanced CT scans provided the CT performed as part 
of a PET–CT is of similar diagnostic quality as a diagnostic CT with IV and oral contrast. As with CT-
imaging, the same imaging technique should be used for each patient’s PET assessment. 
3.3 
Number of Patients and Centers 
Total enrollment of approximately 180 patients is planned for the study.  Approximately 75 patients will 
be enrolled in the dose escalation portion of the study for ALRN-6924 as single agent therapy, and 
approximately 15-25 additional patients per expansion cohort will be enrolled in up to 5 expansion 
cohorts in the expansion part of the study.  The expansion cohort of patients with MDM2 amplified or 
MDM2/CDK4 co-amplified solid tumors is planned to include approximately 10 patients with 
MDM2/CDK4 co-amplification.  In the event that the distribution of patients with MDM2 amplified 
versus MDM2/CDK4 co-amplified tumors becomes imbalanced, the sponsor may temporarily suspend 
enrollment to one group to facilitate enrollment in the other. 
Approximately 15 to 25 clinical sites are planned. 
3.4 
Duration of Study 
The expected accrual phase is approximately 54 months. The expected follow-up phase is approximately 
8 months after the last patient is enrolled, for a total study duration of approximately 62 months.   

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4 
PATIENT POPULATION 
The study will enroll adult or adolescent patients with advanced solid tumors or lymphomas who are 
expected to have WT TP53 and are refractory to or intolerant of standard therapy, or for whom no 
standard therapy exists.  The distinct inclusion/exclusion criteria for each cohort are presented in the 
remainder of this section. 
4.1 
Inclusion Criteria – Phase 1 dose escalation (ALRN-6924 administered as single agent 
therapy) 
Patients must meet all of the following criteria to be considered for participation in this study: 
1. 
Male or female patients age 18 years and older, inclusive, at the time of informed consent 
2. 
Histologically- or cytologically-confirmed solid tumors that are metastatic or 
unresectable or lymphomas.  Standard measures do not exist or are no longer effective for 
these patients. 
3.  
WT TP53 status for relapsing or treatment-refractory solid neoplasms and lymphomas is 
mandatory for patients enrolling at Dose Level 4 and higher in Stage 1 of the DEP as well 
as for all patients enrolled in Stage 2 of the DEP or in the EXP.  In EXP, beginning with 
Amendment 6, TP53 status still must be determined by the central laboratory, but 
confirmation of WT TP53 status is not required for enrollment or initiation of study 
treatment, if the Investigator deems it clinically unacceptable to delay treatment. 
4. 
At least one target lesion that is measurable by RECIST 1.1 in patients with solid tumors 
or by IWG (2014) criteria in patients with lymphoma. 
5. 
ECOG performance status 0-1 
6. 
Predicted life expectancy of ≥3 months 
7. 
Adequate hematologic bone marrow function, measured within 7 days prior to the first 
dose of ALRN-6924, defined as: 
• 
ANC ≥1.5 × 109/L 
• 
Hemoglobin ≥9.0 g/dL 
• 
Platelets ≥100 ×109/L 
8. 
Adequate hepatic function, measured within 7 days prior to the first dose of ALRN-6924, 
defined as: 
• 
In the absence of disease involvement in the liver: bilirubin ≤1.5 times institutional 
ULN as well as AST and ALT ≤2.5 times ULN  
• 
In the presence of disease involvement in the liver: bilirubin ≤2 times ULN as well as 
AST and ALT ≤5 times ULN  
9. 
Adequate renal function, measured within 7 days prior to the first dose of ALRN-6924, 
defined as: 
• 
Urinalysis with no evidence of +2 or higher proteinuria 

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• 
Serum creatinine ≤1.5 times institutional ULN or calculated creatinine clearance ≥50 
mL/min (Cockcroft-Gault formula) 
10. 
Acceptable coagulation profile, measured within 7 days prior to the first dose of ALRN-
6924, defined as: 
• 
PT or INR ≤1.5 times ULN 
• 
aPTT ≤1.5 times ULN 
11. 
Prior anti-cancer therapies must wash-out such that they can neither cause drug-drug 
interaction with ALRN-6924 nor interfere with the anti-cancer evaluation of ALRN-
6924.  Therefore, the wash-out has to meet all the following criteria: 
- 
 patients must have recovered from the previous therapy to Grade 1 or baseline of 
significant toxicities, excluding alopecia, and  
- 
 5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the prior 
anti-cancer therapy and ALRN-6924 do not interfere with each other’s 
metabolism, and 
- 
 5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the patient 
unequivocally progressed during the prior anti-cancer therapy 
Palliative radiotherapy for bone lesions ≤2 weeks prior to the first dose of ALRN-6924 is 
acceptable if acute toxicity has resolved 
12. 
Negative serum or urine pregnancy test within 2 days prior to the first dose of ALRN-
6924 for women of child-bearing potential, defined as a sexually mature woman who has 
not undergone a hysterectomy or who has not been naturally post-menopausal for ≥24 
consecutive months (i.e., who has had menses any time in the preceding 24 consecutive 
months) 
13. 
All patients (males and females) of child-bearing potential must agree to use an effective 
method of birth control (i.e., latex condom, diaphragm, cervical cap, IUD, birth control 
pill, etc.) beginning two weeks before the first dose of ALRN-6924 and for 30 days after 
the last dose of ALRN-6924 
14. 
Ability to understand and willingness to sign a written informed consent form 
15. 
Patients with prostate cancer must continue androgen deprivation therapy, unless such 
therapy was discontinued 6 months prior to first dose of ALRN-6924 
4.2 
Exclusion Criteria – Phase 1 dose escalation (ALRN-6924 administered as single agent 
therapy) 
Patients who meet any of the following criteria at screening or Day -1 will be excluded: 
1. 
Previous treatment with investigational agents that inhibit MDM2 or MDMX activity 
with the following exception: 
Patients previously treated with an MDM2-inhibitor are eligible provided that a 
biopsy taken after completion of the last treatment with an MDM2-inhibitor is 
confirmed as WT TP53 prior to enrollment. 
2. 
Known hypersensitivity to any study drug component 

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3. 
Known and untreated brain metastases.  Patients with brain metastases that have been 
treated and demonstrated to be clinically stable for ≥30 days may be enrolled.  Patients 
with primary CNS malignancies are excluded. 
4. 
Current, clinically significant coagulopathy or platelet disorder, as determined by the 
Investigator  
5. 
History of pulmonary embolism within 6 months prior to the first dose of ALRN-6924 or 
untreated DVT  
6. 
Required concurrent use of anti-coagulants or anti-platelet medication, with the exception 
of aspirin doses ≤81 mg/day, low-dose SC heparin or SC low-molecular-weight heparin 
for DVT prophylaxis, or heparin flushes to maintain IV catheter patency. 
7. 
Patients with pre-existing history of or known cardiovascular risk: 
• 
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). 
• 
Uncontrolled hypertension  
• 
Pre-existing cardiac failure (New York Heart Association class III-IV) 
• 
Atrial fibrillation on anti-coagulants. 
• 
Clinically significant uncontrolled arrhythmias  
• 
Severe valvulopathy. 
• 
Corrected QTc interval on screening ECG ≥450 msec for males and ≥470 msec 
for females (QTc >480 msec for any patient with a bundle branch block). 
8. 
Clinically significant gastrointestinal bleeding within 6 months prior to the first dose of 
ALRN-6924. 
9. 
Clinically significant third-space fluid accumulation (e.g., ascites requiring tapping 
despite the use of diuretics, or pleural effusion that requires tapping or is associated with 
shortness of breath). 
10. 
Pregnant or lactating females. 
11. 
Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision  
of informed consent to participate in this study. 
12. 
Active uncontrolled infection, including HIV/AIDS or hepatitis B or C in the absence of 
hepatocellular carcinoma.  Patients with primary liver cancer that have positive hepatitis 
serology but are not demonstrating active viral hepatitis may be considered for 
enrollment if they meet all other inclusion and no other exclusion criteria. 
13. 
Starting at Dose Level 4 and higher of Stage 1 of the DEP, as well as for all patients 
enrolling in Stage 2 of the DEP or in the EXP, patients with an HPV-positive 
malignancy. 

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14.  
Known history of another primary malignancy that has not been in remission for ≥2 
years.  Non-melanoma skin cancer and cervical carcinomas in situ or squamous 
intraepithelial lesions (e.g., CIN or PIN) are allowed. 
15. 
Any psychological, sociological, or geographical condition that could potentially 
interfere with compliance with the study protocol and follow-up schedule. 
16. 
The required use of any concomitant medications that are predominantly cleared by 
hepatobiliary transporters, OATP members OATP1B1 and OATP1B3, on the day of the 
ALRN-6924 infusion or within 48 hours after an ALRN-6924 infusion. 
17.   
Hereditary angioedema of any severity or history of severe or life-threatening 
angioedema, due to any cause  
4.3 
Inclusion Criteria – Phase 2a dose expansions in PTCL (ALRN-6924 administered as single 
agent therapy) 
1. Male or female patients age 18 years and older, inclusive, at the time of informed consent 
2. A histologically confirmed diagnosis of PTCL based on pathology review at the local 
institution, using the most recent edition of the WHO Classification of Tumors of 
Haematopoietic and Lymphoid Tissues as guidance.  
The pathology sample must be considered to be adequate, meaning that there must be enough 
well-preserved, formalin-fixed biopsy material for the pathologist to be able to perform a 
morphological and immunohistochemical examination so as to in confidence be able to state 
an unequivocal diagnosis of PTCL. Final diagnoses containing caveats such as “suspicious 
of” or “presumably” are considered inadequate for a patient to be enrolled in the trial. In 
addition, a pathology sample must be available for a central pathology read.  
3. Patients must have relapsed or refractory disease after at least one but not more than 7 prior 
systemic anticancer regimens.  
4. WT TP53 status of t-cell lymphoma cells. Beginning with Amendment 6, TP53 status still 
must be determined by the central laboratory, but confirmation of WT TP53 status is not 
required for enrollment or initiation of study treatment, if the Investigator deems it clinically 
unacceptable to delay treatment.  
5. At least one target lesion that is measurable by Revised International Working Group 
Response Criteria for lymphoma patients (IWG 2014 - See Appendix L). Patients with PTCL 
subtypes that are assessed by alternative criteria must have measurable disease in accordance 
with those criteria and be approved by the Medical Monitor. 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (See Appendix A) 
7. Predicted life expectancy of ≥3 months 
8. Adequate hematological bone marrow function, measured within 7 days prior to the first dose 
of ALRN-6924, defined as: 
• 
Absolute neutrophil count (ANC) ≥1.0 x 109/L  

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• 
Platelets ≥50 ×109/L (platelets <50 x 109/L are acceptable if partly caused by 
autoimmune destruction and/or splenomegaly and/or hepatic disease infiltration) 
9. Adequate hepatic function, measured within 7 days prior to the first dose of ALRN-6924, 
defined as: 
• 
Total bilirubin ≤1.5 x upper normal limit, or ≤ 3 x upper normal limit if 
documented hepatic infiltration with lymphoma 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
upper normal limit (≤ 5 x upper normal limit if documented hepatic infiltration 
with lymphoma) 
10. Adequate renal function, measured within 7 days prior to the first dose of ALRN-6924, 
defined as serum creatinine ≤1.5 times institutional ULN, or calculated creatinine clearance 
≥50 mL/min (Cockcroft-Gault formula) 
11. Acceptable coagulation profile, measured within 7 days prior to the first dose of ALRN-6924, 
defined as: 
• 
Prothrombin time (PT) or international normalized ratio (INR) ≤1.5 times ULN 
• 
Activated partial thromboplastin time (aPTT) ≤1.5 times ULN 
12. Prior anti-cancer therapies must wash-out such that they can neither cause drug-drug 
interaction with ALRN-6924 nor interfere with the anti-cancer evaluation of ALRN-6924.  
Therefore, the wash-out has to meet all the following criteria: 
o patients must have recovered from the previous therapy to ≤Grade 1 or baseline of 
significant toxicities, excluding alopecia, and  
o 5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the prior anti-
cancer therapy and ALRN-6924 do not interfere with each other’s metabolism, and 
o  5 half-lives or 4 weeks (whichever is shorter) must have expired, unless the patient 
unequivocally progressed during the prior anti-cancer therapy 
Palliative radiotherapy for bone lesions ≤2 weeks prior to the first dose of ALRN-6924 is 
acceptable if acute toxicity has resolved 
13. Negative serum or urine pregnancy test within 2 days prior to the first dose of ALRN-6924 
for women of child-bearing potential, defined as a sexually mature woman who has not 
undergone a hysterectomy or who has not been naturally post-menopausal for ≥24 
consecutive months (i.e., who has had menses any time in the preceding 24 consecutive 
months) 
14. All patients (males and females) of child-bearing potential must agree to use an effective 
method of birth control (i.e., latex condom, diaphragm, cervical cap, intra-uterine device 
[IUD], birth control pill, etc.) beginning two weeks prior to the first dose of ALRN-6924 and 
for 30 days after the last dose of ALRN-6924 
15. Ability to understand and willingness to sign a written informed consent form 

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4.4 
Exclusion Criteria – Phase 2a dose expansions in PTCL (ALRN-6924 administered as single 
agent therapy) 
1. Previous treatment with investigational agents that inhibit MDM2 or MDMX activity  
2. Relapse within 75 days of autologous bone marrow transplant. 
3. Prior allogeneic stem cell transplantation, unless immunosuppressants are no longer required 
and there is no active graft versus host disease.  
4. Known central nervous system (CNS) lymphoma [computed tomography (CT) or magnetic 
resonance imaging (MRI) scans are required only if brain metastasis is suspected clinically 
5. Known hypersensitivity to any study drug component 
6. Current, clinically significant coagulopathy or platelet disorder, as determined by the 
Investigator 
7. Required concurrent use of anti-coagulants or anti-platelet medication, with the exception of 
aspirin doses ≤ 81 mg/day, low-dose subcutaneous (SC) heparin or SC low-molecular-weight 
heparin for DVT prophylaxis, or heparin flushes to maintain IV catheter patency.  
8. Patients with pre-existing history of or known cardiovascular risk: 
• 
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) 
• 
Uncontrolled hypertension  
• 
Pre-existing cardiac failure (New York Heart Association Class III-IV) 
• 
Atrial fibrillation on anti-coagulants 
• 
Clinically significant uncontrolled arrhythmias 
• 
Severe valvulopathy 
• 
Corrected QT (QTc) interval on screening electrocardiogram (ECG) ≥450 msec for 
males and ≥470 msec for females (QTc >480 msec for any patient with a bundle 
branch block) 
9. Clinically significant gastrointestinal bleeding within 6 months prior to the first dose of 
ALRN-6924 
10. Clinically significant third-space fluid accumulation (e.g., ascites requiring tapping despite 
the use of diuretics; or pleural effusion that requires tapping or is associated with shortness of 
breath) 
11. Pregnant or lactating females 
12. Evidence of serious and/or unstable pre-existing medical, psychiatric, or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision of 
informed consent to participate in this study 
13. Active uncontrolled infection, including HIV/AIDS or Hepatitis B or C  

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14. Known history of another primary malignancy that has not been in remission for ≥1 year.  
Non-melanoma skin cancer and cervical carcinomas in situ or squamous intraepithelial 
lesions (e.g., cervical intraepithelial neoplasia [CIN] or prostatic intraepithelial/intraductal 
neoplasia [PIN]) are allowed. 
15. Any psychological, sociological, or geographical condition that could potentially interfere 
with compliance with the study protocol and follow-up schedule 
16. 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 ALRN-6924 infusion or within 48 hours after an 
ALRN-6924 infusion (see Appendix B) 
17. Hereditary angioedema of any severity or history of severe or life-threatening angioedema, 
due to any cause. 
4.5 
Inclusion Criteria - Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 
Co-amplified Solid Tumors (ALRN-6924 plus palbociclib) 
1. Histologically-confirmed solid tumor malignancy: 
a. for which there is no curative treatment and that is relapsed or refractory following at 
least one prior line of medical therapy; and  
b. that is either MDM2 amplified or MDM2/CDK4 co-amplified, based on local or central 
laboratory testing by NGS, FISH, or CGH. Tissue must be available for analysis at a 
central laboratory, even if enrolling based on alternative (e.g., local or commercial) test 
results. Alternative laboratory results require approval by the Medical Monitor prior to 
enrollment. Specimens must have been obtained after any previous exposure to 
palbociclib or any other CDK4/6 inhibitor. 
2. At least one target lesion that is measurable by RECIST 1.1 or RANO or other appropriate 
response criteria 
3. Males and females aged 12 years and older  
4. ECOG performance status of 0 to 1 
5. Adequate hematopoiesis, defined as: 
a. Absolute neutrophil count ≥1.5 × 109/L  
b. Hemoglobin ≥9.0 g/dL (without transfusions in the past 2 weeks) 
c. Platelets ≥100 ×109/L  
d. Absolute lymphocyte count ≥ 0.5 × 109/L 
6. Adequate hepatic function, defined as:  
a. In the absence of disease involvement of the liver: bilirubin ≤1.5 times institutional ULN, 
and AST and ALT ≤2.5 times ULN   

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b. In the presence of disease involvement of the liver: bilirubin ≤2 times institutional ULN 
and AST and ALT ≤5 times ULN   
7. Adequate renal function, defined as serum creatinine ≤1.5 times institutional ULN, or 
calculated creatinine clearance ≥50 mL/min (Cockcroft Gault formula) 
8. Five half-lives or 4 weeks, whichever is shorter, must have elapsed since any prior anticancer 
agent was administered, unless the patient unequivocally progressed during that therapy and 
the agent would not be expected to interfere with ALRN-6924 or palbociclib metabolism or 
impede clinical assessments 
9. Recovery from the acute toxic effects of all prior therapies to ≤ Grade 1 or baseline, 
excluding alopecia 
10. Provision of informed consent and, where applicable, pediatric assent 
11. Agreement to use acceptable methods of pregnancy prevention, if of child-bearing potential 
4.6 
Exclusion Criteria - Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 
Co-amplified Solid Tumors (ALRN-6924 plus palbociclib) 
1. Tumors with known mutations or deletions in TP53 or Rb  
2. Known hypersensitivity to any component of study medication 
3. Symptomatic or untreated CNS metastases  
4. Pulmonary embolism within the past 6 months or DVT that has not been fully treated. 
5.  Clinically significant cardiovascular risk factors, including: 
• 
myocardial infarction, unstable angina, coronary artery bypass grafting, stenting, 
angioplasty, or acute coronary syndrome in the past 6 months 
• 
New York Heart Association Class III or IV heart failure 
• 
clinically significant uncontrolled arrhythmia 
• 
corrected QT (QTc) interval ≥450 msec for males and ≥470 msec for females 
(QTc >480 msec for any patient with a bundle branch block) 
6. Uncontrolled hypertension 
7. Active, uncontrolled infection, including HIV, hepatitis B, or hepatitis C  
8. HPV-positive malignancy. 
9. Ascites requiring paracentesis or pleural effusion requiring pleurocentesis or causing dyspnea  
10. Hereditary angioedema of any severity or history of clinically significant angioedema, due to 
any cause 
11. Major surgery within 3 weeks prior to the first dose of ALRN-6924   
12. History of another malignancy within the past year, excluding nonmelanoma skin cancers, 
carcinomas in situ, or other malignancies with ≥ 95% 5-year survival  

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13. Pregnant or lactating females 
14. Required use of medications that are primarily cleared by hepatobiliary transporters, 
including organic anion transporters, OATP1B1 and OATP1B3, and bile salt export pump 
(BSEP), unless administration is not required on the day of or within 48 hours following 
ALRN-6924 administration 
15. Required use of medications that are strong inhibitors or moderate to strong inducers of 
CYP3A 
16. Administration of any investigational agent, regardless of indication, within the 2 weeks prior 
to enrollment, unless a minimum of 5 half-lives have elapsed 
17. Any medical, psychological, or social condition that would interfere with patient safety or the 
conduct of the study 
4.7 
Removal of Patients from Study Therapy 
A patient may be removed from the study therapy for a variety of reasons, including: 
• 
Disease progression that is either symptomatic, rapidly progressive, required urgent 
intervention, or associated with a decline in performance status 
• 
Unacceptable adverse event(s) 
• 
Intercurrent illness that prevents further participation 
• 
Patient refusal to continue treatment through the study and/or consent withdrawal for study 
participation 
• 
Patient unable or unwilling to comply with study requirements 
• 
Pregnancy or failure to use adequate birth control 
• 
General or specific changes in the patient’s condition that render the patient unacceptable for 
further treatment in this study in the judgment of the Investigator 
Under no circumstance will care of a withdrawn patient be adversely affected by a decision to withdraw 
or be withdrawn from the study. 
4.8 
Patient Replacement 
Any patient who completes screening and does not receive a dose of ALRN-6924 (single agent cohorts) 
or at least one dose each of ALRN-6924 and palbociclib (MDM2 amplification and MDM2/CDK4 co-
amplification cohort) will be replaced.  A patient in the dose escalation portion of the study or a safety run 
in group who discontinues the study prior to completion of the first cycle for reasons other than safety, or 
who does not receive all required doses in the first cycle for reasons other than safety, will be replaced.  A 
patient in the dose expansion portion of the study who discontinues study participation prior to the 
completion of the first cycle of treatment for any reason or who does not receive all required doses in the 
first cycle may be replaced.  Patients who are not confirmed by the central laboratory to have met all 
molecular requirements for their given cohort may be replaced.  

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5 
TREATMENT PLAN 
5.1 
Study Drug Description 
ALRN-6924 
The study drug for ALRN-6924-1-01 is the investigational agent ALRN-6924.  Details on the 
administration, dispensing, return, and destruction of ALRN-6924 will be provided in the Pharmacy 
Binder. 
ALRN-6924 drug product is a frozen or refrigerated liquid product supplied in single-use glass vials in a 
single dose strength of 75 mg in 5.0 mL, dissolved in 20 mM sodium phosphate, 240 mM trehalose, 
300 ppm Polysorbate 20, pH 7.5. Each vial contains recoverable 5.0 mL and is filled with formulated 
ALRN-6924 to 5.5 ± 0.2 mL.  ALRN-6924 for Injection is stored as frozen product at -15º to -25° C or 
refrigerated product at 2º to 8° C. 
Palbociclib 
For the Phase 2a cohort with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors, palbociclib 
will be provided to patients as capsules for oral use.   
Palbociclib will be administered on an outpatient basis.  Patients will be provided with a diary to record 
time of palbociclib administration on each dosing day.  In order to assess treatment compliance, the 
numbers of palbociclib capsules that were dispensed and returned by the patient will be recorded.  Any 
dose reductions or interruptions, and the reason for these actions, will also be recorded.  
5.2 
Preparation of ALRN-6924 
Specific instructions for acquisition and storage of ALRN-6924 and preparation of the final dosing 
solution will be provided in the Pharmacy Binder.  Briefly, ALRN-6924 is introduced into an IV infusion 
bag containing D5W; this will be known as ALRN-6924 Dosing Solution and will be provided by the site 
pharmacy for administration to the patient.  ALRN-6924 Dosing Solution will be labeled with the ALRN-
6924-1-01 Patient Identification Number.  The investigative staff will confirm this information and its 
relevancy to the intended patient.  The start of the ALRN-6924 infusion must begin within 6 hours of 
dilution into 250-mL D5W, and the infusion bag shall remain at room temperature until use.  
5.3 
Study Drug Administration 
The investigational agent ALRN-6924 as well as palbociclib (IBRANCE®) will be provided by Aileron 
and distributed to clinical sites.  Patients should begin treatment with study drug within 21 days following 
the start of clinical screening. Issues that would cause treatment delays should be discussed with 
Sponsor’s Medical Monitor.   
Treatment of patients in the dose escalation and the dose expansion phases of the study 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 receiving clinical benefit despite evidence of suspected or confirmed PD may 
continue on study after a discussion between the Principle Investigator and Medical Monitor.  

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ALRN-6924 will be administered by IV infusion in D5W. The pre-defined dose will be calculated for 
each patient based on body weight at the start of each cycle. During the first two cycles, ALRN-6924 
should be administered in the morning to allow observation of delayed infusion reactions. 
Phase 1 Dose Escalation: 
Treatment 
Regimen 
Infusion 
Days 
Infusion Time 
Additional notes 
DR-A 
1, 8, 15 of a 
28-day cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or oral 
fluids (500 mL – 1000 mL) should be administered, 
unless clinically contraindicated. 
DR-A-2 
1, 8, 15 of a 
28-day cycle 
2 hours (±15 min) 
At the end of the infusion, IV fluids (saline) or oral 
fluids (500 mL – 1000 mL) should be administered, 
unless clinically contraindicated. Administer 
dexamethasone (4 mg orally or IV) approximately 4 
hours after the end of the infusion in Cycles 1 and 2, 
and thereafter at the discretion of the investigator.  
DR-B 
1, 4, 8, 11 of 
a 
21-day 
cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or oral 
fluids (500 mL – 1000 mL) should be administered, 
unless clinically contraindicated. 
In DEP, ALRN-6924 will not be administered outside of the planned schedule in Cycle 1 (i.e., there are 
no planned windows for dose days).  Follow-up visits on non-dosing days have windows, however, at the 
Investigator’s discretion, it may be necessary to conduct a study visit on an alternative day than described 
in this schedule in order to protect the safety, rights, or welfare of the patient.  If this is the situation, the 
Investigator will confer with and obtain approval from the Medical Monitor.   
Patients in the DEP who remain on study treatment for 2 years or longer may have their dosing frequency 
reduced (i.e., Days 1 and 15 of a 28-day cycle for DR-A and Days 1 and 8 of a 21-day cycle for DR-B), at 
the discretion of the investigator.  In the event that disease control is lost, the original administration 
schedule may be resumed, at the discretion of the investigator. 

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Phase 2a Dose Expansion: 
Treatment 
Regimen 
Drug and 
Dose Level 
Dosing 
Days 
Infusion Time 
Additional notes 
DR-A 
ALRN-6924 
3.1 mg/kg 
1, 8, 15 of a 
28-day cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically 
contraindicated. 
DR-B 
ALRN-6924 
2.7 mg/kg 
1, 4, 8, 11 of 
a 21-day 
cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically 
contraindicated. 
DR-C 
 
ALRN-6924 
3.1 mg/kg  
[If 3.1 mg/kg is 
not well 
tolerated, 
lower doses 
may be tested 
starting at dose 
levels of -25%]   
1, 3, 5 of a 
21-day cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically 
contraindicated. 
Combination 
with 
palbociclib 
ALRN-6924 
3.1 mg/kg 
[If 3.1 mg/kg is 
not well 
tolerated, up to 
two dose 
reductions of 
25% may be 
tested]   
1, 8, 15 of a 
28-day cycle 
1 hour (±15 min) 
At the end of the infusion, IV fluids (saline) or 
oral fluids (500 mL – 1000 mL) should be 
administered, unless clinically 
contraindicated. 
 
Palbociclib 
100 mg 
[If 100 mg is 
not well 
tolerated, 
reduction to a 
75 mg dose 
may be tested.] 
1-21 of a 
28-day cycle 
Oral 
Palbociclib should be administered with food.  
On days when both drugs are administered 
(Days 1, 8, and 15 of each cycle), palbociclib 
should be administered at least 6 hours after 
the infusion of ALRN-6924.  
 

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5.4 
Management of Toxicities 
5.4.1 
Toxicities Related to ALRN-6924 
Usual supportive medicines used as standard-of-care are allowed, with the exception of growth factors 
during DEP Cycle 1. All supportive medications and medications to treat toxicities must be recorded in 
the electronic case report form (eCRF). 
5.4.1.1 Management of Infusion-Related Reactions 
For the management of Grade 1-2 infusion-related reactions:  
• 
Stop the infusion for 15–30 minutes. 
• 
Measure vital signs at least once every 5 minutes until symptoms abate. 
• 
Consider administering diphenhydramine 25–50 mg IV or equivalent.  
• 
If symptoms abate, re-start the infusion at one-half the previous rate. 
• 
Additional medical measures, such as the administration of selective anti-histamines (e.g., 
cimetidine 300 mg or ranitidine 50 mg IV) or corticosteroids (e.g., dexamethasone 20 mg IV) 
may be considered for reactions that do not abate after 15 minutes. 
• 
If symptoms do not abate 30 minutes after the administration of medical measures, 
discontinue the day’s ALRN-6924 treatment. 
In the case of a prior infusion-related reaction controlled by above medical management, subsequent 
ALRN-6924 infusions should include premedication at least 30 minutes before the start of ALRN-6924 
infusion. 
For the management of Grade 3+ infusion-related reactions:  
• 
Stop the infusion. 
• 
Measure vital signs at least once every 5 minutes until symptoms abate. 
• 
Consider administering the following: 
o Diphenhydramine 50 mg IV 
o Cimetidine 300 mg or ranitidine 50 mg IV 
o Dexamethasone 20 mg IV 
o Epinephrine 0.5 mg SC 
o Albuterol inhaler as needed for bronchospasm 
• 
Additional agents may be administered per institutional guidelines for the treatment of 
infusion-related reactions. 
Patients experiencing Grade 3 hypersensitivity reactions that require hospitalization or any Grade 4 
hypersensitivity reactions that are related to ALRN-6924 infusion should be discontinued from study 
treatment and not rechallenged. 

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5.4.1.2 Angioedema 
Follow standard clinical practice when suspecting angioedema symptoms during treatment with 
ALRN-6924. If the administration of antihistamines and corticosteroids does not resolve symptoms, 
consider the administration of icatibant, a bradykinin B2-receptor inhibitor approved in the US and 
Europe for the treatment of hereditary angioedema. In the event of signs of airway obstruction, 
epinephrine has to be immediately available and the patient must be in the care of a clinician who can 
provide emergency airway management. 
Patients being treated with ALRN-6924 should be educated about the symptoms of angioedema and urged 
to tell their care team immediately, should such symptoms develop.   
5.4.1.3 Management of Tumor Lysis Syndrome (TLS) 
There is a potential for TLS in patients with lymphoma, especially those with large tumor burden, pre-
dose elevated lactate dehydrogenase and leukocyte counts, renal dysfunction, or dehydration.  TLS can be 
caused by treatment-induced abrupt cancer cell disintegration.  It is usually observed shortly after 
initiating treatment.  
Laboratory TLS is defined as a 25% increase in the levels of serum uric acid, potassium, or phosphorus or 
a 25% decrease in calcium levels.  
Prophylaxis and management of TLS for at risk patients during this clinical trial must include : 
• 
Laboratory assessments of the blood prior to each ALRN-6924 administration during Cycle 1:  
o Electrolytes, including potassium, phosphorus, and calcium 
o Creatinine 
o Uric acid 
o Lactate dehydrogenase 
• 
Administration of allopurinol or an alternative uric acid-lowering agent throughout Cycle 1. 
• 
Antiemetics should be optimized, to prevent poor oral intake and fluid losses from 
vomiting.  Hydration status should be monitored closely and intravenous fluids should be 
administered as indicated, to prevent or treat dehydration.  
• 
ALRN-6924 must be withheld, if TLS is suspected, and not resumed until electrolyte aberrations 
and renal function have stabilized and uric acid has been reduced to within normal limits. 
• 
Patients should be hospitalized for closer monitoring and management, if clinically indicated in 
the judgment of the investigator. 
These actions should be continued beyond Cycle 1, if the patient remains at risk, in the judgment of the 
investigator. 
Additional prophylaxis and/or management should be implemented in accordance with local standard of 
care practices. 
 

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5.4.2 
Toxicities Related to Palbociclib 
For patients in the palbociclib combination cohort, palbociclib-related toxicities should be managed as 
described in the current approved US prescribing information. All supportive medications and 
medications to treat toxicities must be recorded in the eCRF. 
5.5 
Registering and Enrolling Patients on Study, Assignment of Dose Level 
5.5.1 
Patient Registration 
Prior to registration and any study-specific evaluations being performed, adult patients must have given 
written informed consent; for pediatric patients, written informed consent from parent(s) or legal guardian 
and pediatric assent for the study must have been provided.  All patients must have completed the pre-
study evaluations.  Patients must meet all of the eligibility requirements listed in Section 4.  Each patient 
will be assigned a unique identification code prior to enrollment. 
See the Study Operations Binder for further information on Patient Enrollment. 
5.5.2 
Staggered Cohort Enrollment Scheme for Dose Level 1 (DEP) 
A staggered cohort enrollment scheme will be employed in the first dose cohort (Dose Level 1), in which 
each patient completes one week of study treatment before the next patient will be enrolled in this cohort.  
There will be no mandated waiting period between patients enrolled in Dose Level 2 and higher. 
5.5.3 
Assignment of Dose Level (DEP) 
Cohorts of three to six patients will receive ALRN-6924 per dose level and per dose regimen, i.e. DR-A, 
DR-A-2 and DR-B.  At the discretion of the Investigator and Medical Monitor, a fourth patient may be 
enrolled in the initial group of 3 patients per dose regimen (DR) to help manage patient allocation across 
multiple sites. If this occurs, the first 3 patients to complete Cycle 1 in the current DR will be used to 
assess dose limiting toxicities.  However, all available data from the 4th patient will be reviewed at the 
time of the dose level and regimen Safety Review Meeting (Refer to Section 8.10.1). In the event that a 
drug-related DLT is observed in one of the first 3 patients of a dose level in a dose regimen, and after 
discussion among the Investigators and Sponsor’s Medical Monitor, additional patients will be enrolled 
into the study for a total of 6 patients at the same dose level in the same dose regimen. 
5.6 
Dose Escalation Criteria (DEP) 
In the absence of >33% of patients experiencing a drug-related DLT, escalation to the next dose level for 
a given treatment arm may proceed when all of the following have occurred: 
• 
At the completion of Cycle 1 (treatment cycle = 28 days for DR-A and DR-A-2 or treatment 
cycle = 21 days for DR-B), 
• 
The Safety Review Meeting is convened during which the Safety Review Committee (SRC), 
consisting of the Investigators and Sponsor’s Medical Monitor, has reviewed all available 
safety data for all patients in the cohort and confirms that the next planned dose level is 
appropriate; and  
• 
The Sponsor Medical Monitor issues written documentation of the decision to proceed to the 
next planned dose level of a dose regimen.  

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It is important to note that despite the absence of >33% of patients experiencing a DLT, the next dose 
level may be less than the planned dose level if the Investigators and Sponsor’s Medical Monitor agree 
that a more conservative dose escalation approach is warranted or would be in the best interest of the 
patients. The SRC may hold the dose (e.g., stop dose escalation) at their discretion and enroll additional 
patients until sufficient safety data are obtained to determine escalation of the current dose level or to 
confirm a certain dose as an MTD or OBD. 
5.7 
Planned Dose Levels 
5.7.1 
Dose Levels for the Dose Escalation Portion of the Study 
In the Dose Escalation portion of the study, increasing dose levels of ALRN-6924 will be evaluated in 
cohorts of 3-6 DLT-evaluable patients per dose regimen.  Patients enrolled in Cohort 1 receive ALRN-
6924 at Dose Level 1 (0.16 mg/kg).  Based on allometric scaling, at 0.16 mg/kg dose in humans, the 
predicted AUC (50 µg•hr/mL) is approximately 9% of the rat AUC at STD10 and approximately 6% of the 
AUC at the monkey HNSTD as described in Section 1.4. 
In the absence of DLT in >33% of DLT-evaluable patients in either DR, subsequent cohorts of 3 to 6 
patients will receive escalated doses until the MTD or an OBD is established for each dose regimen.  
A 2-stage dose escalation design will be employed.  During the initial Stage 1 Escalation Phase, 100% 
dose increments will be utilized until ≥1 of 3 patients in a cohort experiences any Grade ≥2 AE that is at 
least possibly related to study drug.  Study drug-related AEs Grade ≥2 occurred in DL-4A (fatigue) and in 
DL-3B (neutropenia).  Therefore, per protocol, Stage 2 has been implemented for subsequent dose 
escalations starting with DL-5A and DL-4B. Dose escalation will continue using 3-patient cohorts and the 
modified Fibonacci sequence (i.e., 67%, 50%, 40%, 33%), until the MTD or an OBD is established. As 
two DLTs have occurred in DR-7A (hypotension and hepatobiliary laboratory abnormalities), there will 
be no further dose escalation in DR-A. A new modified infusion regimen was tested (DR-A-2) starting at 
dose level 7A-2 (=4.4 mg/kg body-weight).  As two DLTs have occurred in DR-7A-2 (anemia and 
neutropenia), there will be no further escalation in DR-A-2. 
Figure 9: Dose Level and Dose Regimen Schematic 
 

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The observation of DLT(s) will be used to make individual patient determinations regarding dose 
reductions, interruptions or discontinuation throughout the course of the trial, but DLTs occurring during 
Cycle 1 will be used to inform safety and tolerability assessments for dose escalation decisions. 
If DLTs are observed in the first cohort, the dose will be de-escalated to Dose Level -1.  If DLTs are 
observed at Dose Level -1, the dose will be de-escalated to Dose Level -2.  If DLTs are observed at Dose 
Level -2, other dose levels may be considered and implemented after discussions among the Investigators 
and Sponsor’s Medical Monitor. 
It is anticipated that at least 3 patients will be treated at each dose level per treatment arm.  If no patients 
experience a DLT, then the subsequent 3 patients will be treated at the next planned dose level.   
If DLT is observed in ≥2 of 3 patients in either treatment DRs at any dose level, no further dose escalation 
will occur in that DR, and the current dose will be defined as the maximum administered dose (MAD).  
If DLT is observed in 1 of 3 patients in a cohort at any dose level, then up to 6 patients total will be 
enrolled at that same DR at that dose level.  If DLT is observed in ≥2 patients in the expanded cohort, 
then no further dose escalation will occur, and the current dose will be defined as the MAD, unless the 
SRC decides that there is sufficient clinical uncertainty about the DLTs that warrants the enrollment of up 
to 6 additional patients.  In the event of additionally enrolled patients, if a DLT is observed in 33% or 
more DLT-evaluable patients in the entire cohort, then no further dose escalation will occur, and the 
current dose will be defined as the MAD for the dosing regimen under consideration.  After the MAD is 
defined, either the previously administered lower dose will be expanded to a total of 6 patients, or an 
intermediate (between the MAD and the next lower dose level) will be investigated in up to 6 patients.  
The highest dose tolerated without DLT in at least 5 of 6 patients (i.e. <33% of DLT-evaluable patients 
experiencing a DLT) in a cohort from one treatment arm will be defined as the MTD for that treatment 
arm. Additional patients may be added to further explore the MTD or OBD prior to expansion. 
Based on review of available safety and PK data during this and other studies with ALRN-6924, dose 
escalation or modification steps may be adjusted (i.e. increased or decreased) by the SRC to limit the 
number of patients exposed to sub-therapeutic dose levels as well as to ensure patients’ safety. Additional 
patients may be added to further explore safety at a dose level or to confirm a certain dose as an MTD or 
OBD.  
5.7.2 
Dose Levels for the Expansion Portion of the Study 
The EXP will enroll up to 5 distinct groups of patients with specific solid tumors and/or lymphomas to 
further investigate the clinical safety profile and potential efficacy of ALRN 6924 at the MTD, OBD, or 
an alternative dosing regimen. PTCL has been selected as one of the EXP groups to be further studied; up 
to 3 cohorts in PTCL may be studied in order to determine the optimal dosing regimen.  Another Phase 2a 
EXP group will include patients with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors who 
will receive ALRN-6924 in combination with palbociclib.   
Phase 2a Expansion in PTCL 
Two DLTs were observed at DL-7A (hypotension and hepatobiliary laboratory abnormalities) rendering 
DL-7A the maximum administered dose whereas in DL-6A, only one DLT was observed (fatigue) in six 
DLT-evaluable patients. Furthermore, a complete remission has been observed in a PTCL patient at 
DL-5A (2.1 mg/kg). Therefore, the first selected dose and schedule for the Phase 2a expansion in PTCL is 

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3.1 mg/kg on Days 1, 8, and 15 of a 28 day cycle (DL-6A).  Alternative dosing regimens to be tested may 
include 2.7 mg/kg on Days 1, 4, 8, and 11 of a 21 day cycle (DR-B) and 3.1 mg/kg on Days 1, 3, and 5 of 
a 21 day cycle (DR-C). Six to 8 patients will be enrolled in DR-C in a run-in part and the treating 
investigators, along with the Medical Monitor, will review safety and tolerability through Cycle 1 prior to 
opening the full DR-C expansion cohort. Lower dose levels for DR-C, in 25% reductions in the starting 
dose, may be assessed if the safety and tolerability of 3.1 mg/kg are not acceptable. Should this occur, 6-8 
patients will again be enrolled into a run-in part and the treating investigators and Medical Monitor will 
meet again to review all patients prior to opening the full DR-C expansion cohort.  For each dose level 
assessed during the run-in part, the SRC will use the DLTs defined in Phase 1 as a guide for determining 
safety. 
Phase 2a Expansion in MDM2 amplified or MDM2/CDK4 co-amplified solid tumors 
ALRN-6924 and palbociclib have not previously been co-administered in humans.  Therefore, for the 
Phase 2a cohort of patients with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors, a safety 
run-in group of 6-8 patients will first be enrolled and evaluated by the sponsor and the primary 
investigators before further patients are permitted to enroll.  The SRC will use the DLTs defined in 
Phase 1 and the toxicity profile of palbociclib (in accordance with the package insert) as a guide for 
assessing safety.   
Enrollment of the first 3 patients in this cohort will be separated in time by at least one week each, to 
assess for unexpected acute toxicities related to administration of the treatment regimen.  Patients will 
receive ALRN-6924 at the previously determined recommended Phase 2 dose for the once-weekly 
administration schedule (3.1 mg/kg on Days 1, 8, and 15) and palbociclib at an oral dose of 100 mg daily 
for 21 days (one dose level below the approved oral dose of 125 mg) in a 28-day cycle.  In the event that 
this regimen is not determined to be safe or tolerable at these dose levels, the dose of ALRN-6924 will be 
decreased by 25% and/or the dose of palbociclib will be decreased by one dose level (to 75 mg/day), as 
needed based on the pattern of toxicities encountered, and an additional 6-8 patients will be assessed in a 
safety run-in using the reduced dose level, before further enrollment is permitted.  Subsequent reductions 
of the ALRN-6924 dose by 25% may be implemented if safety and tolerability are still not acceptable.  
The decision to begin palbociclib below the approved dose level is based on the frequency of required 
dose reductions, often due to neutropenia.  The SRC may consider adjusting to the approved palbociclib 
dose, if palbociclib-related toxicities are not prohibitive and patient benefit is expected to outweigh risk.  
Once the safety run-in is complete, all subsequent patients will be enrolled at the recommended dose 
level. 
5.7.3 
Intra-Patient Dose Escalation- Phase 1 Dose Escalation 
A patient’s dose may be increased to that of a cohort that completed the first cycle without dose-limiting 
toxicity in ≥ 33% of DLT-evaluable patients and that has not exceeded the MTD.  Intra-patient dose 
escalations will be allowed provided that the patient completed at least two treatment cycles and did not 
experience study medication-related toxicity greater than Grade 2 (except for alopecia, electrolyte 
disturbances responsive to correction within 24 hours, diarrhea, nausea, fatigue and vomiting that 
responds to standard medical care).  Approval for intra-patient dose escalation must be obtained from the 
Medical Monitor. 

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5.8 
Dose and Schedule Adjustments for Toxicity 
5.8.1 
Dose Modifications – Phase 1 dose escalation (ALRN-6924 administered as single agent 
therapy) 
In the event a Grade 4 AE considered related to ALRN-6924 is observed, the patient must be discontinued 
from study treatment.  Exceptions include Grade 4 neutropenia lasting <3 days, and emesis, diarrhea or 
electrolyte abnormalities that resolve within 2 days on optimum treatment.  For these exceptions, 
treatment may be delayed for up to 2 weeks to allow resolution of the toxicity (i.e., return to Grade ≤1 or 
baseline), followed by re-treatment at a reduced dose.  Two dose reductions are permitted; a third dose 
reduction will require evidence of clinical benefit and approval by the Medical Monitor. Relevant labs 
should be repeated as medically indicated. 
In the event a Grade 3 AE considered related to ALRN-6924 is observed (exceptions are Grade 3 fatigue, 
nausea, emesis, diarrhea or clinically insignificant electrolyte abnormalities that resolve within 2 days on 
optimum treatment), treatment may be delayed for up to 2 weeks to allow resolution of the toxicity, 
followed by re-treatment at a reduced dose.  Two dose reductions are permitted, a third dose reduction 
will require evidence of clinical benefit and approval by the Medical Monitor. Relevant labs should be 
repeated as medically indicated. 
Dose modifications for re-treatment following related Grade 3 and Grade 4 AEs (as permitted): patients 
will be re-treated at the preceding dose level (per Figure 9).   
For other clinically significant AEs, treatment may be delayed by up to 2 weeks to allow for the 
resolution of AEs to an acceptable level, and may continue treatment at a reduced dose level as described 
above at the discretion of the Investigator in consultation with Sponsor’s Medical Monitor.  If a patient 
experiences multiple AEs, decisions on dosing delay or dose reduction will be based on the most severe 
AE.  Any patient who experiences recurrent, clinically significant AE after one dose reduction may 
undergo one additional dose reduction.  Patients who continue to experience clinically significant AEs 
after a 2-week delay or the maximum allowed number of dose reductions will be discontinued from the 
study. 
Adverse events considered for dose reduction should not include the events assessed by the Investigator 
as exclusively related to underlying disease or other medical condition or concomitant treatment.  A 
patient who experiences an AE considered related to ALRN-6924 that does not meet the requirement for 
discontinuation may continue on study if the patient is receiving clinical benefit and/or the Investigator 
feels continued participation is in the best interest of the patient.  In such cases, at the Investigator’s 
discretion and in agreement with Sponsor’s Medical Monitor, the dose for a patient may be reduced as 
described above.   
A patient who experiences a DLT must continue treatment at a reduced dose level, or discontinue 
ALRN-6924 treatment (if Grade 4 related AE), as described above at the discretion of the Investigator 
and in agreement with Sponsor’s Medical Monitor until disease progression or unacceptable toxicity.  
Once the dose has been reduced for a patient, it may not be re-escalated. 

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5.8.2 
Dose Modifications – Phase 2a dose expansions in PTCL (ALRN-6924 administered as 
single agent therapy) 
In the event a non-hematologic Grade 4 AE considered related to ALRN-6924 is observed, the patient 
must be discontinued from the study. Exceptions include emesis, diarrhea or electrolyte abnormalities that 
resolve within 2 days on optimum treatment.  For these exceptions, treatment may be delayed for up to 2 
weeks to allow resolution of the toxicity (i.e., return to Grade ≤1 or baseline), followed by re-treatment at 
a reduced dose. Relevant labs should be repeated as medically indicated.  
In the event a non-hematologic Grade 3 AE considered related to ALRN-6924 is observed (exceptions are 
Grade 3 fatigue, nausea, emesis, diarrhea or clinically insignificant electrolyte abnormalities that resolve 
within 2 days on optimum treatment), treatment may be delayed for up to 2 weeks to allow resolution of 
the toxicity, followed by re-treatment at a reduced dose. Relevant labs should be repeated as medically 
indicated. 
For hematologic toxicities, patients must discontinue treatment with ALRN-6924 if  
• 
Neutrophil counts < 0.5 x 109/L for > 5 days, or 
• 
Platelet counts < 10 x 109/L, or 
• 
Hemoglobin < 6g/dL (despite RBC transfusion or Erythropoiesis-Stimulating Agent (ESA) 
administration) 
Patients must interrupt treatment if  
• 
Neutrophil counts < 0.5 x 109/L for ≤ 5 days, or 
• 
Platelet counts < 25 x 109/L and >10 x 109/L, or 
• 
Hemoglobin < 8 g/dL and > 6 g/dL 
After resolution of hematologic toxicity (i.e., return to Grade ≤1 or baseline), patients may continue at a 
reduced dose. Relevant labs should be repeated as medically indicated. 
Following related Grade 3 and Grade 4 AEs (as permitted), the dose for re-treatment will be reduced by 
25% intervals (e.g., if the dose is 3.1 mg/kg, the dose will be reduced sequentially to 2.3 mg/kg and 1.7 
mg/kg).  Two dose reductions are permitted, a third dose reduction will require evidence of clinical 
benefit and approval by the Medical Monitor. 
5.8.3 
Dose Modifications – Phase 2a Dose Expansion in MDM2 Amplified or MDM2/CDK4 Co-
amplified Solid Tumors (ALRN-6924 plus palbociclib) 
Dose modifications of ALRN-6924 will be as described in Section 5.8.1. Dose modifications of 
palbociclib should be made in accordance with the current approved US prescribing information.   
In the event that palbociclib administration must be discontinued, the patient may continue to receive 
ALRN-6924 as a study participant until one of the criteria for treatment discontinuation has been met. 
However, if discontinuation of ALRN-6924 is required, patients will be considered to have discontinued 
study treatment. Those patients may continue to receive palbociclib treatment at the Investigator’s 
discretion.  

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5.9 
Toxicity, DLT and MTD Evaluation 
5.9.1 
Toxicity Grading Criteria 
Toxicity grading is based on NCI CTCAE v4.03. 
5.9.2 
Definition of Dose-Limiting Toxicity  
A DLT will be defined as any Grade ≥3 AE that is considered to be possibly, probably, or definitely 
related to the study drug, with the following exceptions: (1) for fatigue, nausea, emesis, diarrhea or 
mucositis, only Grade ≥3 AE that do not respond within 48 hours to standard supportive/pharmacological 
treatment will be considered DLT; (2) for electrolyte imbalances, only Grade ≥3 AE that do not respond 
to correction within 24 hours will be considered DLT; (3) for infusion reactions, only a Grade 3 reaction 
which caused hospitalization or Grade 4 will be considered a DLT.  In addition, specific hematologic 
DLTs are defined as:  
• Thrombocytopenia – Grade 4 of any duration, Grade 3 for ≥7 days, or Grade 3 associated with clinically 
significant bleeding 
• Neutropenia – Grade 4 for ≥3 days, or any Grade ≥3 febrile neutropenia  
The above criteria will be used to make individual patient determinations regarding dose reductions, 
interruptions or discontinuation throughout the course of the trial, but DLTs occurring during Cycle 1 will 
be used to inform safety and tolerability assessments for dose escalation decisions. 
5.9.3 
Definition of Maximum Tolerated Dose 
The MTD is defined as the dose at which ≤1 of 6 patients experiences a treatment-related toxicity that 
qualifies as a DLT, with the next higher dose having ≥2 of up to 6 patients experiencing a DLT.  
The MTD will not be established until all patients enrolled in the cohort have completed Cycle 1, 
discontinued treatment or had a dose reduction.  Previously established tolerability of a dose level will be 
reevaluated if toxicities that would have been DLTs in Cycle 1 are observed in later cycles. 
5.9.4 
Definition of Optimal Biological Dose (OBD) 
For each treatment arm, the safety review committee might identify an OBD for a selected patient 
population before the MTD is reached.  Such OBD would be derived from the evaluation of available 
safety, PK, PD, and preliminary efficacy information from the dose escalation portion of the study. 
5.10 Concomitant Medications and Therapies 
5.10.1 Permitted and Recommended Medications 
Any changes in documented, permitted concomitant medications taken within 28 days of beginning 
treatment with ALRN-6924, or at the beginning of the clinical trial, or permitted concomitant medications 
added during the time the patient is participating in this study (through End-of-Treatment Visit or receipt 
of a subsequent therapy) must be recorded in the eCRF.  All supportive medications and medications to 
treat toxicities as listed in Section 5.4 must be recorded in the eCRF.  
Patients treated with ALRN-6924 have experienced nausea and vomiting.  The administration of 
antiemetics, including 5HT3 antagonists, is recommended prior to and for 72 hours following 

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ALRN-6924 administration.   For patients receiving palbociclib, additional antiemetic administration may 
be required. 
Patients who experience neutropenia after Cycle 1 of DEP or at any time during EXP may receive 
myeloid growth factors at the discretion of the investigator. 
5.10.2 Prohibited Medications and Medications Requiring Special Consideration 
Other agents and treatments as outlined in Section 4, including concurrent anti-tumor therapy of any kind 
or any other investigational agent, are excluded.  In the event that a patient is deriving clinical benefit 
from study treatment, but requires concurrent anticancer surgery or radiation therapy, that patient may 
continue on the study with permission of the Medical Monitor.  The PI and medical monitor will 
determine the required duration of ALRN-6924 and/or palbociclib interruption, to allow for such 
treatments.  Efficacy measures will be censored, as of the time of any such permitted concurrent therapy.  
Although they are not prohibited, it is strongly recommended that alternative antihypertensive agents be 
used in place of ACE inhibitors and ARBs during treatment with ALRN-6924. It cannot be excluded that 
concomitant treatment with these agents and ALRN-6924 may increase the risk for developing 
angioedema.  Note that this does not change the requirement to hold ARBs for 48 hours following the 
administration of ALRN-6924, due to a known pharmacokinetic interaction that decreases clearance of 
the ARB. 
Any concomitant medications that are predominantly cleared by hepatobiliary transporters, OATP 
members OATP1B1 and OATP1B3, on the day of the ALRN-6924 infusion and within 48 hours after an 
ALRN-6924 infusion are prohibited (Appendix B), including the sartan class of angiotensin receptor 
blockers (ARBs). 
For patients with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors who are receiving 
ALRN-6924 in combination with palbociclib, strong CYP3A inhibitors and moderate to strong CYP3A 
inducers are prohibited.  Patients should not consume grapefruit products while receiving palbociclib. 
5.11 Packaging, Labeling, and Storage 
The ALRN-6924 study vials will be labeled according to the local law and legislation.  A copy of the 
labels will be filed and stored in the trial master files and can be made available to the study sites upon 
request. 
ALRN-6924 for Injection is stored as frozen product at -15º to -25° C or refrigerated product at 2º to 
8° C. 
Palbociclib should be stored as described in the current approved US prescribing information. 
5.12 Drug Accountability 
The Principal Investigator is responsible for ensuring accountability for the investigational agent 
ALRN-6924, including reconciliation of drugs and maintenance of drug records. 
Upon receipt of ALRN-6924, the clinical study site will check for accurate delivery and acknowledge 
receipt by signing (or initialing) and dating the documentation provided and returning it to the Sponsor or 
Sponsor’s designee.  A copy will be retained in the Investigator site file. 

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The receipt, dispensing, administration, and return of ALRN-6924 will be recorded on the appropriate 
drug accountability forms, and an accurate accounting will be available for verification by the Sponsor 
monitor at each monitoring visit.  
Investigational agent accountability records will include: 
• 
Confirmation of delivery to the site 
• 
Inventory at the site  
• 
Dispensing for each patient 
• 
Return or alternative disposition of unused study drug 
• 
Dates, quantities, batch numbers, expiry dates, and the Patient Identification Number for the 
study.  
The Sponsor monitor will periodically review the investigational agent accountability forms to verify 
drug accountability and compliance. Drug accountability and destruction instructions are outlined in the 
Pharmacy Binder. 

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6 
STUDY PROCEDURES 
6.1 
Schedule of Study Events 
The schedule of study activities (including assessments, tests, exams, disease assessments, collection of 
tissue specimens, and study drug administration) beginning with molecular screening and continuing 
throughout the study are provided in the appendices starting with Appendix C. 
Phase 1 dose escalation: During the first 2 dose levels, patients will receive ALRN-6924 on Days 1, 8, 
and 15 of a 28-day cycle.  Starting with DL 3, patients in treatment DR-A and DR-A-2 (starting at DL7) 
will continue being treated once a week on Days 1, 8, and 15 of a 28-day cycle, whereas patients in DR-B 
will be treated twice a week, on Days 1 and 4, 8 and 11 of a 21-day cycle.  Dose escalation proceeds 
based on safety parameters and review as described in Sections 5.5.3, 5.6, and 8.10.1 and each DR is 
independent of each other.  All data regardless of DR and DL will be collated and available for each 
Safety Review Meeting. 
Phase 2a dose expansion:  
• 
Patients with PTCL: up to 3 single agent dosing regimens will be tested: DR-A (Days 1, 8, and 15 
of a 28-day cycle); DR-B (Days 1, 4, 8, and 11 of a 21-day cycle); and DR-C (Days 1, 3, and 5 of 
a 21-day cycle).   
• 
Patients with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors: ALRN-6924 
(DR-A) will be administered in combination with palbociclib in a 28-day cycle (see Appendix I 
and Appendix J).  
Refer to the Pharmacy Binder for detailed instructions on how to prepare and administer ALRN-6924. For 
instructions on administration of palbociclib, refer to the current approved US prescribing information. 
6.2 
Informed Consent and Pediatric Assent 
Informed consent will be collected prior to any study specific procedures.  This may be accomplished by 
using an Informed Consent Form (ICF) specific to molecular screening followed by an ICF for the main 
study, or may be a combined form covering both molecular screening and the main study.  
For any cohort in which adolescents are eligible to enroll, pediatric assent may be required in accordance 
with local laws and regulations.  Informed consent must be provided by a legally-acceptable 
representative if the age of majority has not been reached.  A minor who reaches the age of majority 
during study participation must be reconsented to confirm their agreement with continued participation. 
6.3 
Biopsies 
A fresh or archival biopsy taken pre-dose must be sent to the central laboratory for TP53 and/or MDM2 
and CDK4 amplification testing. See Section 3.2 and the Laboratory Manual for details. For patients in 
the PTCL expansion cohorts, an additional pre-treatment tumor sample is required to be available for 
central pathology read (if requested). 
In the Phase 2a EXP PTCL cohorts, optional biopsies will be taken for PD purposes as well as for TP53 
testing: during screening, during treatment, and at times of suspected progression.  In the palbociclib 
combination cohort, if a biopsy is taken for any reason during the study, the samples may be used for 
further analysis.  See the Laboratory Manual for details. Samples might be submitted for whole exome 
sequencing (with paired germline samples) and RNA sequencing (RNAseq), and results will be compared 

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between pre-treatment and on-treatment, and times of suspected progression. Tumor samples will be 
examined for markers of disease response and resistance. Protein expression via immunohistochemistry 
and RNA expression via quantitative RT-PCR may be examined on specimens obtained prior to 
beginning treatment, during treatment with ALRN-6924, and then upon suspected progression. 
6.4 
Germline DNA 
To be collected via a buccal swab only for patients in Phase 2a EXP PTCL cohorts who consent to 
optional biopsies. See the Laboratory Manual for details. 
6.5 
Medical and Disease History 
The medical history is to include demographic information, cancer history, including disease duration, 
previous treatment regimens, and toxicities, as well as information about the patient’s non-malignancy-
related history and all prior surgeries. 
6.6 
Vital signs 
Includes blood pressure, pulse, respiration rate, and body temperature. Collection times are indicated in 
the schedule of events. Additional vital signs will be collected at the discretion of the investigator. 
6.7 
Electrocardiograms 
Screening and predose ECGs (if required) are to be performed in triplicate (5-10 min between readings). 
ECGs are to be performed after the patient has been supine for at least 10 minutes.  All ECGs should be 
performed with the patient in the same physical position.  Postdose ECGs (if required) are to be 
performed in triplicate (5-10 min between readings) only if patient has a QTc that is a) >500 msec; b) 
increased by 60 msec over pre-dose; or c) decreased by 50 msec below pre-dose recording. 
6.8 
Physical Examination 
Full physical examination to be performed at Screening, Day 1 pre-dose, and End of Treatment; all other 
physical examinations (if required) may be symptom-directed.  Weight to be collected at Screening and 
on Day 1 (or up to 3 days prior to Day 1) of each cycle.  Height is to be obtained only at the Screening 
visit. 
6.9 
Laboratory Assessments  
Laboratory assessments to be performed locally may include:  
• 
Clinical chemistry (glucose, calcium, albumin, total protein, sodium, potassium, CO2, 
chloride, phosphate, BUN [blood urea nitrogen], serum creatinine, uric acid, alkaline 
phosphatase, ALT, AST, LDH, total and direct bilirubin). 
• 
Hematology (complete blood count, platelets and differential). 
• 
Urinalysis (dipstick measurement [pH, specific gravity, protein, glucose, ketones, nitrite, 
leukocyte esterase] with microscopic analysis, if results of the dipstick indicate additional 
testing required). 
• 
Coagulation (PT, INR, aPTT).   
• 
Serum or urine pregnancy test (Beta human chorionic gonadotropin [β-hCG]) for women of 
child-bearing potential. 

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• 
At select visits, lymphocyte subset testing will be performed (B-cells, T-cells including CD4 
and CD8, natural killer [NK] cells).  
• 
C-reactive protein, fibrinogen, and reticulocytes will also be collected at select visits. 
• 
HPV testing of tumor tissue from cancers likely to be HPV-positive: to be performed 
dependent upon cancer type, including (but not limited to) cervical cancer, oropharyngeal 
cancer, head and neck squamous cell cancers or anal cancer.  
• 
HIV, Hepatitis B and C testing 
6.10 Disease Assessments/Imaging 
RECIST 1.1- or iRECIST- (for solid tumor patients), RANO- (for glioblastoma patients), or IWG 2014- 
(for lymphoma patients) compliant imaging scans, photographs, physical examination, and/or laboratory-
based assays (e.g., prostate specific antigen) for patients with relevant disease indications will be obtained 
at baseline (within 21 days of Cycle 1 Day 1) and for objective anti-tumor activity as outlined below. The 
same type of imaging, physical examination, or laboratory-based assay procedure should be used for each 
assessment for a patient.  In EXP, all study images must be available to be sent for central imaging read, 
if requested. 
After dosing commences, perform tumor assessment as follows:  
• 
DR-A, DR-A-2, combination (ALRN-6924 plus palbociclib):  Images will be obtained prior to 
the start of Cycle 3 and every other cycle thereafter, e.g., prior to Cycles 5, 7, and 9. 
• 
DR-B, DR-C:  Images will be obtained prior to the start of Cycle 4 and every third cycle 
thereafter, e.g., prior to Cycles 7, 10, and 11.   
• 
In DEP, after 1 year of treatment, assessments will be obtained at approximately 3 month 
intervals. After 2 years of treatment, assessments will be obtained at approximately 4 month 
intervals or per standard of care. In EXP, the frequency of imaging will not change after 1 year 
of treatment. 
• 
End of Treatment assessments are required only if the patient did not have a tumor assessment 
within the prior 6-8 weeks.  
6.11 Concomitant Medications  
Concomitant medications (current medications and those taken within 28 days of Cycle 1, Day 1) through 
the end of treatment visit or until start of subsequent anticancer therapy.  
6.12 PK and PD Assessments   
Refer to the Laboratory Binders for specimen collection, processing, storage, and shipment procedures.   
Blood samples for PK and PD assessments will be collected at the timepoints shown in the tables below. 
Patients who are already enrolled in the expansion and consent to this testing will have blood drawn at 
their next available cycle (i.e. if the next available cycle is Cycle 4, they will follow the PK/PD Cycle 1 
testing at Cycle 4 [with the exception of germline DNA and cfDNA testing which remains on the below 
schedule], and will follow the below indicated Cycle 2 testing at Cycle 5).  

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DR-A, DR-A-2 (ALRN-6924 single agent therapy) 
Screening 
PK 
PD 
During screening 
 
cfDNA 
Cycle 1 
PK 
PD 
Day 1 
 
within one hour before start of 
infusion (SOI) 
X 
MIC-1 
CTC (select sites only) 
Germline DNA (EXP only) 
End of Infusion (EOI) (+5 min) 
X 
 
30 min after EOI (± 5 min) 
X 
 
1 hr after EOI (±5 min) 
X 
 
2 hr after EOI (±10 min) 
X 
 
4 hr after EOI (±10 min) 
X 
MIC-1 
CTC (select sites only) 
8 hr after EOI (±2 hours) 
X 
MIC-1 
CTC (select sites only) 
Day 2 
 
24 hours (±4 hr) after SOI day 
prior 
X 
MIC-1 
CTC (select sites only) 
Day 3 
(DEP only) 
48 hours (±4 hr) after SOI  
X 
MIC-1 
 
Cycle 2  
PK 
PD 
Day 15 
EOI (+5 min) 
X 
 
1 hr after EOI (±5 min) 
X 
 
4 hr after EOI (±10 min) 
X 
 
Day 16 
(DEP only) 
24 hours (±4 hr) after SOI day 
prior 
X 
 
Cycle 5 
PK 
PD 
Day 1 
within one hour before SOI 
 
cfDNA 
End of Treatment 
PK 
PD 
End of Treatment 
 
cfDNA 
 

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DR-B (ALRN-6924 single agent therapy) 
Screening 
PK 
PD 
During screening 
 
cfDNA 
Cycle 1 
PK 
PD 
Day 1 
 
within one hour before SOI 
X 
MIC-1 
CTC (select sites only) 
Germline DNA (EXP only) 
EOI (+5 min) 
X 
 
30 min after EOI (± 5 min) 
X 
 
1 hr after EOI (±5 min) 
X 
 
2 hr after EOI (±10 min) 
X 
 
4 hr after EOI (±10 min) 
X 
MIC-1 
CTC (select sites only) 
8 hr after EOI (±2 hours) 
X 
MIC-1 
CTC (select sites only) 
Day 2 
 
24 hours (±4 hr) after SOI day 
prior 
X 
MIC-1 
CTC (select sites only) 
Day 3 
(DEP only) 
48 hours (±4 hr) after SOI  
X 
MIC-1 
 
Day 4 
within one hour before SOI 
X 
MIC-1 
Cycle 2  
PK 
PD 
Day 11 
 
EOI (+5 min) 
X 
 
1 hr after EOI (±5 min) 
X 
 
4 hr after EOI (±10 min) 
X 
 
Day 12 
(DEP only) 
24 hours (±4 hr) after SOI day 
prior 
X 
 
Cycle 5 
PK 
PD 
Day 1 
within one hour before SOI 
 
cfDNA 
End of Treatment 
PK 
PD 
End of Treatment 
 
cfDNA 
 

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DR-C (ALRN-6924 single agent therapy) 
Screening 
PK 
PD 
During screening 
 
cfDNA 
Cycle 1 
PK 
PD 
Day 1 
 
within one hour before SOI 
X 
MIC-1 
Germline DNA 
CTC (select sites only) 
EOI (+5 min) 
X 
 
30 min after EOI (± 5 min) 
X 
 
1 hr after EOI (±5 min) 
X 
 
2 hr after EOI (±10 min) 
X 
 
4 hr after EOI (±10 min) 
X 
MIC-1 
CTC (select sites only) 
8 hr after EOI (±2 hours) 
X 
MIC-1 
CTC (select sites only) 
Day 2 
(optional) 
 
24 hours (±4 hr) after SOI day 
prior 
 
MIC-1 
CTC (select sites only) 
Day 3 
 
within one hour before SOI 
X 
MIC-1 
EOI (+5 min) 
X 
 
Day 5 
within one hour before SOI 
X 
MIC-1 
EOI (+5 min) 
X 
 
1 hr after EOI (±5 min) 
X 
 
2 hr after EOI (±10 min) 
X 
 
Day 8  
Any time  
X 
MIC-1 
Cycle 2  
PK 
PD 
Day 5 
within one hour before SOI 
X 
 
EOI (+5 min) 
X 
 
1 hr after EOI (±5 min) 
X 
 
2 hr after EOI (±10 min) 
X 
 
Cycle 5 
PK 
PD 
Day 1 
within one hour before SOI 
 
cfDNA 
End of Treatment 
PK 
PD 
End of Treatment 
 
cfDNA 
 

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ALRN-6924 plus palbociclib 
Timepoint 
PK 
PD 
ALRN-6924 
Palbociclib 
During screening 
 
 
 
cfDNA 
Cycle 1 
Day 1 
 
within one hour before start of ALRN-6924 
infusion (SOI) 
X 
 
 
End of Infusion (EOI) (+5 min) 
X 
 
 
30 min after EOI (± 5 min) 
X 
 
 
1 hr after EOI (±5 min) 
X 
 
 
2 hr after EOI (±10 min) 
X 
 
 
4 hr after EOI (±10 min) 
X 
 
 
Day 2 
 
24 hrs (±2 hr) after EOI Day 1/ 
18 hrs (±2 hr) after Day 1 palbociclib dose 
X 
X 
 
Day 8  
within one hour before ALRN-6924 SOI 
X 
X 
 
EOI (+5 min) 
X 
X 
 
Day 15 
within one hour before ALRN-6924 SOI 
X 
X 
 
EOI (+5 min) 
X 
X 
 
Day 22 
Any time 
X 
X 
 
Cycle 5 
Day 1 
within one hour before SOI 
 
 
cfDNA 
End of Treatment 
End of Treatment 
Any time 
 
 
cfDNA 
 
6.13 End of Treatment and End of Study 
Approximately 30 days (+/- 5 days) after the last dose of study drug, an end of treatment visit will be 
conducted. For patients in Phase 1, this visit will be the same as the end of study. Patients in Phase 2 will 
remain on study and be followed for survival and subsequent therapies.  

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7 
STATISTICAL CONSIDERATIONS 
Full details will be included in the Statistical Analysis Plan. 
7.1 
General Considerations 
The primary objectives of this Phase 1/2a study are to determine the MTD or OBD and DLT(s) of ALRN-
6924 administered by IV infusion on Days 1, 8 and 15 (DEP DR-A and DR-A-2) of a 28-day cycle or 
Days 1, 4, 8, 11 (DEP DR- B) of a 21-day cycle, in patients with advanced solid tumors or lymphoma and 
to further investigate the clinical safety profile and efficacy of ALRN-6924 (administered alone or in 
combination with other agents) in expansion cohorts (Phase 2a) which will include an additional dosing 
cohort of ALRN-6924 administered by IV infusion on Days 1, 3, and 5 (DR- C) of a 21-day cycle.  
Statistical analyses will be descriptive in nature and will account for all dose levels and regimens studied.  
Where applicable, analyses will include a description of adolescent versus adult data. 
7.2 
Patient Disposition and Characteristics 
The baseline characteristics of patients enrolled will be summarized.  All patients who received study 
treatment will be accounted for, including patients who died or withdrew from study treatment during the 
study.   
7.3 
Safety Analysis 
The safety population will include all patients who have received at least one dose of ALRN-6924. 
Adverse events, vital sign measurements, clinical laboratory information and concomitant medication 
usage will be tabulated.  All toxicities will be summarized by severity based on the NCI CTCAE version 
4.03 and relationship to treatment.  Serious adverse events will be listed separately.  Graphical displays 
will be provided where useful in the interpretation of results. Statistical analyses will be descriptive in 
nature and will account for all dose levels and regimens studied. 
7.4 
Pharmacokinetic Analysis 
Levels of ALRN-6924 and its metabolite (and other agents given in combination with ALRN-6924) will 
be measured in blood samples collected at specific timepoints.  Pharmacokinetic data will be tabulated 
and summarized by individual patient and collectively by dose level for each dose regimen.  Graphical 
displays will be provided where useful in the interpretation of results. 
7.5 
Pharmacodynamic Analysis 
Levels of p53, MDM2, MDMX, p21 and caspase will be measured in tumor specimens collected before 
beginning treatment, during Cycle 1 or Cycle 2 and at suspected disease progression.  MIC-1 and CTCs 
will be measured in blood samples.  Pharmacodynamic effects on the composition of cell free DNA from 
blood will be evaluated. Pharmacodynamic data will be tabulated and summarized by individual patient 
and collectively by dose level.  Graphical displays will be provided where useful in the interpretation of 
results. 
7.6 
Clinical Activity Analysis 
To evaluate clinical activity, response rates and duration of response based on RECIST 1.1, IWG 2014, 
RANO, iRECIST, or other appropriate or exploratory criteria will be analyzed.   

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In DEP, the efficacy evaluable population will consist of patients who: 
• 
Received at least one dose of ALRN-6924 at a dose level at least 0.8 mg/kg per infusion 
• 
Have at least one post-baseline evaluation or had clinical progression and  
• 
Are TP53 wild type or indeterminate (as assessed by the central lab, and if not assessed by central 
laboratory, as assessed by the local laboratory)  
In the single agent EXP cohorts, the efficacy evaluable population will consist of patients who: 
• 
Received at least one dose of ALRN-6924  
• 
Have at least one post-baseline evaluation or had clinical progression and  
• 
Are TP53 wild type (as assessed by the central lab)  
In the EXP cohort of patients with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors, the 
efficacy evaluable population will consist of patients who: 
• 
Received at least one dose each of ALRN-6924 and palbociclib 
• 
Have at least one post-baseline evaluation or had clinical progression and  
• 
Are confirmed to have MDM2 amplification (with or without CDK4 co-amplification) with TP53 
and Rb wild type (as assessed by the central lab) 
A descriptive analysis of other evidence of anti-tumor activity or other clinical benefit will be provided 
based on clinical, radiographic or other appropriate assessment of efficacy or clinical anti-tumor activity.   
Overall response rate, duration of response, and time to response will be assessed in DEP as well as in 
EXP.  
Additional clinical activity analyses in the Phase 2a dose expansion will include OS and PFS and OS at 
1 year. Time-to-event endpoints will be calculated from the time of first administration of ALRN-6924 
(Day 1) until the stated event or end of study.  

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8 
SAFETY 
The Investigator and the Sponsor are responsible for monitoring the safety of patients who have entered 
the study.  To capture the most potentially relevant safety information during a clinical trial, it is 
important that Investigators record accurate AE terms on the eCRF.   
8.1 
Adverse Event Definitions 
8.1.1 
Adverse Event 
An AE includes any noxious, pathological, or unintended change in anatomical, physiological, or 
metabolic functions as indicated by physical signs, symptoms, and/or laboratory changes occurring in any 
phase of the clinical study whether or not temporally associated with the administration of study 
medication and whether or not considered related to the study medication. This definition includes an 
exacerbation of pre-existing medical conditions or events, intercurrent illnesses, hypersensitivity 
reactions, drug interactions, or clinically significant laboratory findings. 
An AE does not include the following: 
• 
Medical or surgical procedures, e.g., tooth extraction, transfusion, surgery (The medical condition 
that leads to the procedure is to be recorded as an AE.) 
• 
Pre-existing conditions or procedures present or detected at the start of the study that do not 
worsen 
• 
Hospitalization for elective surgeries or for other situations in which an untoward medical event 
has not occurred 
• 
Abnormal laboratory value, unless it is clinically significant according to the Investigator, 
requires intervention, or results in a delay, discontinuation or change in the dose of study drug  
• 
Overdose of study drug or concomitant medication unaccompanied by signs/symptoms; if 
sign/symptoms occur, the final diagnosis should be recorded as an AE. 
• 
Pregnancy by itself, unless a complication occurs during pregnancy leading to hospitalization; in 
this case, the medical condition that leads to the hospitalization is to be recorded as the AE. 
• 
A significant worsening of the disease under investigation including death which is captured as an 
efficacy parameter in this study and, thus, is not recorded as an AE.  
8.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is defined as an adverse event that results in any of the following 
outcomes: 
• 
Death 
• 
Life-threatening adverse experience (i.e., immediate risk of death from the event as it occurred; 
this does not include an adverse event that, had it occurred in a more serious form, might have 
caused death) 
• 
Persistent or significant disability/incapacitation 
• 
Inpatient hospitalization or prolongation of existing hospitalization 

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• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based on medical judgment, they may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Hospitalizations due to the underlying disease will not be reported as an SAE unless there is reason to 
suspect a causal relationship with the study drug. 
8.1.3 
Unexpected Adverse Event 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the ALRN-6924 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; or, is not 
consistent with the risk information described in the protocol or elsewhere. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the Investigator’s 
Brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the Investigator’s 
Brochure listed only cerebral vascular accidents.  
"Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions that are 
mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of ALRN-6924 but are not specifically mentioned as occurring with ALRN-
6924. 
8.2 
Adverse Event Reporting Period 
The AE reporting period begins from the date of the first study drug administration and ends 30 days after 
the last dose of study drug or a subsequent anticancer therapy is started, whichever occurs first.  See 
Section 8.4 for information about reporting SAEs. Information regarding the follow up of AEs can be 
found in Section 8.5. 
8.3 
Recording of Adverse Events 
Each AE should be recorded in standard medical terminology on the AE eCRF page.  Whenever possible, 
the AE should be evaluated and reported as a diagnosis rather than as individual signs or symptoms.  For 
example, cough, runny nose, sneezing, sore throat, and head congestion should be reported as ‘upper 
respiratory infection’. If a definitive diagnosis is not possible, the individual signs and symptoms should 
be recorded.  Dates of start (onset) and stop (recovery), action taken, and outcome will be recorded in the 
AE eCRF page. 
An abnormal laboratory value will not be considered as an AE unless it is 1) assessed as clinically 
significant by the Investigator, 2) requires intervention, or 3) results in a delay, discontinuation or change 
in the dose of study treatment.  A clinically significant abnormal laboratory value will not be considered 
an AE if it is determined to be related to the study condition or concomitant conditions, e.g., diabetes, of 
which the Investigator was previously aware and have not worsened.  An abnormal laboratory value 
considered as an AE will be recorded on the AE page or module. 
The Investigator will evaluate all AEs with regard to maximum intensity and relationship to study drug, 
as follows. 

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8.3.1 
Maximum Intensity 
Maximum intensity should be assigned using one of the severity grades as outlined in the NCI CTCAE 
v4.03; if the AE is not specifically listed in CTCAE v4.03, use the following grades: 
• 
Grade 1: mild 
• 
Grade 2: moderate 
• 
Grade 3: severe/disabling 
• 
Grade 4: life-threatening 
• 
Grade 5: death 
8.3.2 
Relationship to Study Treatment 
The degree of certainty with which an AE is attributed to study treatment (or alternative causes, e.g., 
natural history of the underlying diseases, concomitant therapy, etc.) will be determined by how well the 
event can be understood in terms of known pharmacology of ALRN-6924 (or agents administered in 
combination with ALRN-6924) and/or reaction of similar nature previously observed with ALRN-6924 
or similar drugs.  Each AE will be assigned one of the following five categories: 
• 
Unrelated:  There is not a temporal relationship to study drug administration (e.g., too early, too late, 
study drug not taken), or there is a reasonable causal relationship to another drug, concurrent illness, 
or circumstance. 
• 
Unlikely related:  There is a temporal relationship to study drug administration, but there is not a 
reasonable causal relationship between study drug and the AE (i.e., it is doubtful the AE is related to 
study drug); could be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
• 
Possibly related:  There is a reasonable temporal sequence from administration of the drug (e.g., 
occurred in a time frame relevant to administration of study drug, including the outcome after 
withdrawal of study medication, if applicable); or for which the possibility of the study drug being the 
causative factor (e.g., existence of similar reports attributed to the suspected drug and its analogues; 
reactions attributable to the pharmacological effect) could not be excluded, although other factors 
such as underlying disease, complications, concomitant drugs, or concurrent treatment are 
presumable. 
• 
Probably related:  There is a reasonable temporal sequence from administration of the drug 
(including the course after withdrawal of the drug); and for which the possibility of factors other than 
the drug, such as underlying disease, complications, concomitant drugs, or concurrent treatment, 
could not be excluded as the cause. 
• 
Definitely related:  Follows a clear temporal sequence from administration of the study drug; could 
not be possibly explained by the known characteristics of the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient; disappears or decreases on 
cessation or reduction in dose of the study drug; reappears or worsens when the study drug is re-
administered; or follows a response pattern known to be associated with administration of the study 
drug. 

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8.4 
Adverse Event Reporting 
Each AE is to be reported by the Investigator as serious or non-serious according to the definitions above. 
This classification that determines the regulatory reporting procedures to be followed is described in 
Table 5. 
Table 5:  Reporting Guidelines for Adverse Events 
Any SAE, regardless of relationship to study treatment that occurs during therapy or within 30 days after 
the last dose of study treatment must be reported to the Sponsor within 24 hours after the site becomes 
aware of the event.  The Investigator is encouraged to discuss with the study Medical Monitor any 
adverse experiences for which the issue of reportability is unclear or questioned.  The initial report should 
be followed by submission of a more detailed SAE Report within 4 working days of the site’s knowledge 
of the event.  
If the SAE occurs more than 30 days following administration of the last dose of study treatment, SAEs 
should be reported only if considered related to study treatment. In the event of patient death, the reason 
for death should be recorded as the SAE, with ‘death’ recorded as the outcome on the SAE eCRF module. 
The SAE also will be recorded as an AE on the AE eCRF page.  Note: the SAE Report is different from 
the AE eCRF page. In areas of both forms where the same data are reported, the forms will be completed 
in a consistent manner. For example, the same term should be used for the AE on both forms, with the 
same start and stop dates, action taken, outcome, etc.  
An SAE Report should be prepared with as much available information concerning the event as possible 
so that a written report can be filed with the appropriate regulatory authorities. If causality cannot be 
determined definitively at the time of the SAE occurrence, it is important to notify the Sponsor within the 
timeline stated above, and to attribute the relationship as ‘Not Assessable’ (only applicable for the initial 
SAE Report). When new significant information is obtained and the outcome and attribution of the event 
is known, the Investigator will communicate this in a follow-up SAE Report.  This relevant information 
will be provided in a timely manner to allow reporting to regulatory authorities within the required 
reporting period.  Any SAE follow-up information requested by the Sponsor should be provided in a 
timely manner. 
As necessary, the SAE Report should be accompanied by relevant pages from the eCRFs, e.g., medical 
history, AEs, concomitant medications.  Additional information may be requested by Sponsor in an 
expedited manner to ensure that the initial reporting of the SAE made to the regulatory authorities 
complies with the required time frame.  The Sponsor may be required to collect and report additional 
Gravity of AE 
Reporting Time to Sponsor 
Type of Report 
Serious 
Within 24 hours after the site 
becomes aware of the event 
Initial SAE Report 
Within 4 working days after the 
site becomes aware of the event 
Completed SAE Report 
Non-Serious 
Per AE eCRF page 
Completed AE  
eCRF page 

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information to the regulatory authorities in a follow-up report, containing a final evaluation of the event, 
including copies of hospital reports, autopsy reports, or other relevant information.  
The Sponsor will provide information regarding SAEs and IND safety reports to Investigators for 
notification of IRBs in accordance with FDA regulations. 
8.5 
Adverse Event and Serious Adverse Event Follow-Up 
All AEs and SAEs observed while a patient is receiving study treatment should be followed until 
resolution, return to baseline, or it is deemed that further recovery is unlikely. For patients who have 
discontinued study treatment, all AEs and SAEs that occur within 30 days after the last administration of 
study treatment or withdrawal from the study must be reported unless the patient starts new anticancer 
therapy.  Any AE or SAE deemed related to study drug should be followed until resolution or 
stabilization, or until the patient starts new therapy.  All measures required for AE management and the 
ultimate outcome of the AE will be recorded in the source document and eCRF. 
For SAEs occurring from the patient’s first administration of study treatment, during the study or within 
30 days of the last administration of study drug, the Investigator should submit follow-up reports to the 
Sponsor regarding the status of the SAE and the patient’s subsequent course.  Follow-up reports should be 
submitted until the SAE has subsided, until the condition stabilizes (in the case of persistent impairment), 
the patient receives alternative therapy, or the patient dies.   
8.6 
Ongoing Safety Evaluation 
During DEP, a study safety evaluation will be conducted on a regular (monthly) basis by teleconference, 
led by the Sponsor’s Medical Monitor and participating Principal Investigators.  All available dose 
exposure, dose-limiting toxicity, AE/SAE profiles and clinical laboratory abnormalities, and other safety 
measures will be reviewed during each convened meeting.  Patient accrual will not be interrupted during 
the regularly scheduled safety evaluations.  
The same process will be followed for the assessment of safety run-ins conducted during the EXP; 
however, these safety evaluations will be triggered by the accrual of a target number of safety evaluable 
patients, rather than occurring on a monthly basis. 
8.7 
Pregnancy 
Any pregnancy diagnosed during the study, or that occurs within 30 days after stopping study medication, 
must be reported immediately to the Investigator. Pregnancy, in and of itself, is not regarded as an adverse 
event, unless there is suspicion that study medication may have interfered with the effectiveness of a 
contraceptive medication. If the patient becomes pregnant while on-study, the study drug should be 
immediately discontinued. Pregnancy information about a female patient or a female partner of a male 
patient should be reported immediately from the time the Investigator first becomes aware of a pregnancy 
or its outcome. This will be performed by the Investigator completing a Pregnancy Form. 
Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for medical 
reasons, outcome of stillbirth, congenital anomaly/birth defect, or serious adverse event in the mother will 
be recorded as an SAE and will be reported as described in Section 8.4. 

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8.8 
Medication Errors 
A medication error for this study is defined as any accidental incorrect administration of a medicinal 
product.  The error may be related to the administration of a wrong medication, nature of the medication, 
route of administration, dosage or frequency of the treatment as specified in this protocol (including 
omission of one or more administrations). 
• 
Medication errors with concomitant medication treatment will not be recorded in the CRF 
unless they result in an AE. 
• 
Medication errors with the study medication that result in an AE will be captured as an AE in 
the CRF.  
• 
Medication errors with the study medication resulting in an overdose, incorrect route of 
administration, or administration with the incorrect study drug will be reported to Safety Desk 
as soon as they are known regardless of whether or not a subsequent AE has occurred. 
8.9 
Overdose 
An overdose with ALRN-6924 for this clinical trial is defined as an accidental or intentional overdose 
with ALRN-6924 regardless of whether it is associated with an AE (even if not fulfilling a seriousness 
criterion), and is to be reported to Safety Desk within 24 hours from the time the Investigator first 
becomes aware of its occurrence following the same process as described for SAEs. 
There is no known antidote available in case of ALRN-6924 overdose.  Overdose should be managed 
aggressively with close monitoring and administration of prophylactic and symptomatic therapies to 
prevent or correct potential side effects. 
For information regarding overdose of palbociclib, refer to the current approved US prescribing 
information.  
8.10 Data and Safety Review Process 
8.10.1 Review Process  
This study is a Phase 1/2a dose escalation study designed to determine the safety and the MTD or OBD of 
ALRN-6924 in patients with advanced solid tumors or lymphoma.  Therefore, each dose escalation will 
be based on observed toxicities and AEs.  The safety of ALRN-6924 within each patient cohort will be 
reviewed prior to initiation of the next cohort.  Escalation to the next dose level may proceed in the 
absence of DLT when all of the following have occurred: 
• 
At the completion of Cycle 1 (DR-A or DR-A-2, treatment cycle = 28 days and DR-B, 
treatment cycle = 21 days),  
• 
The Safety Review Meeting has been convened, during which the Safety Review Committee, 
consisting of the Investigators and Sponsor’s Medical Monitor, has reviewed and considered 
all available safety data for all patients in the cohort and confirms that the next planned dose 
level is appropriate; and  
• 
The Sponsor Medical Monitor issues written documentation of the decision to proceed to the 
next planned dose level.  

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In Phase 2a EXP, an additional dosing regimen will be explored in the PTCL cohorts. Six to 8 patients 
will be enrolled in DR-C in a run-in part and the treating investigators, along with the Medical Monitor, 
will review safety and tolerability through Cycle 1, prior to opening the full DR-C expansion cohort.  
Lower dose levels for DR-C may be assessed if the safety and tolerability of 3.1 mg/kg are not acceptable. 
Should this occur, 6-8 patients will again be enrolled in to a run-in part and the treating investigators and 
Medical Monitor will meet again to review all patients, prior to opening the full DR-C expansion cohort. 
In the Phase 2a EXP cohort with MDM2 amplified or MDM2/CDK4 co-amplified solid tumors who will 
receive ALRN-6924 in combination with palbociclib, a safety run-in group of 6-8 patients will first be 
enrolled to determine the optimal dosing regimen for the combination.  Safety and tolerability will be 
evaluated by the sponsor and the primary investigators before further patients are permitted to enroll.   
Ongoing safety monitoring during the study will be provided through frequent teleconferences.  The 
Investigators, clinical research staff, and Sponsor’s Medical Monitor will review toxicities and AEs for all 
patients via regularly scheduled teleconference.  Schedule and frequency of teleconferences may be 
adjusted to reflect enrollment rate and safety observations.   
8.10.2 Oversight Responsibilities 
The Sponsor will be responsible for routine monitoring of this study.  The Sponsor also will be 
responsible for ensuring that ongoing communication is maintained between the Sponsor’s Medical 
Monitor, Investigators and clinical research staff at each site, emphasizing the need for vigilance, 
particularly in the areas of safety and adherence to eligibility criteria.  The Sponsor will ensure that all 
safety, AE and efficacy data are readily available and shared among the clinical sites.  The Sponsor will 
also coordinate teleconferences to review safety information and document decisions regarding 
determination of MTD, DLT and dose escalation, as well as any decisions related to the exploration of 
DR-C in PTCL cohorts, and the combination of ALRN-6924 and palbociclib in the MDM2/CDK4 
amplified solid tumor cohort.   
The Sponsor’s Medical Monitor will review the safety information as it becomes available on an ongoing 
basis for each patient. The Sponsor’s Medical Monitor will review all SAEs occurring during the study 
and ensure that reports are provided to all clinical sites and the FDA, in compliance with FDA guidelines.   
The Sponsor is obligated to report the progress and safety of the study annually to the FDA. 

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9 
STUDY MANAGEMENT 
9.1 
Investigator Responsibilities 
9.1.1 
Data Management 
The Investigator is responsible for ensuring completion and maintenance of adequate and accurate eCRFs 
and source documentation. Source documentation constitutes original records, which may include: 
progress notes, medication administration records, laboratory reports, discharge summaries, etc. All 
eCRFs should be completed in their entirety with source documents and other printed records stored in a 
confidential and locked location. The Investigator must sign the Investigator’s statement in each patient’s 
eCRF indicating that the data reported are accurate. 
9.1.2 
Protocol Adherence 
Each Investigator must adhere to the protocol as detailed in this document and agrees that any changes to 
the protocol must be approved by the Sponsor prior to seeking approval from the IRB. Each Investigator 
will be responsible for enrolling only those patients who have met protocol eligibility criteria. 
9.1.3 
Study Drug Accountability 
The Investigator is responsible for study drug provided to his/her site.  All investigational study drug, 
ALRN-6924, required for completion of this study will be provided by the Sponsor.  The recipient will 
acknowledge receipt of the drug indicating shipment content and condition.  Damaged supplies will be 
replaced.  Accurate records of all study drug dispensed from and returned to the study site are to be 
maintained.  The study site must supply a copy of their drug destruction policy to the Sponsor before 
authorization for destruction can be granted. 
9.2 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, protocol 
adherence, site procedures, integrity of the data, and applicable laws and/or regulations. At regular 
intervals during the study and following completion of the study, the Sponsor’s study monitors will 
contact the study site via visits to the site, telephone calls, and letters in order to review study progress, 
eCRF completion, and address any concerns or questions regarding the study conduct. During monitoring 
visits, the following aspects of study conduct will be carefully reviewed: Patient recruitment, informed 
consent of patients, patient compliance with study procedures, source data verification, drug 
accountability, use of concomitant therapy by patients, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
9.3 
Audits and Inspections 
The Sponsor and its designees, a regulatory authority, or an IRB (or any designees of these organizations) 
may visit the study site at any time during the study or after completion of the study to perform audits or 
inspections.  The purpose of a sponsor audit or regulatory inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these activities 
were conducted according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor immediately if contacted by a regulatory agency 
about an inspection at their site. 

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9.4 
Protocol Amendments 
Any amendments to the protocol will be prepared by the Sponsor.  With the exception of amendments to 
address immediate safety concerns, all amendments must be submitted to the IRB for approval prior to 
implementation. In some instances, an amendment requires changes to the informed consent form, which 
also must be submitted for IRB approval prior to administration to patients. If any changes to the eCRF 
are required, the Sponsor will issue supplemental or revised eCRF pages in the electronic data capture 
system. 
9.5 
Record Keeping 
9.5.1 
Health Insurance Portability Accountability Act of 1996 
The Investigator agrees to comply with all applicable federal, state, and local laws and regulations 
relating to the privacy of patient health information, including, but not limited to, the Standards for 
Individually Identifiable Health Information, 45 Code of Federal Regulations (CFR) Parts 160 and 164 
(the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation). The 
Investigator shall ensure that study patients authorize the use and disclosure of protected health 
information in accordance with HIPAA Privacy Regulation and in a form satisfactory to the Sponsor.  
9.5.2 
Financial and Regulatory Disclosures 
The Investigator shall provide to the Sponsor sufficient accurate financial information to support 
submission of complete and accurate financial certification or disclosure statements to the FDA. The 
Investigator shall also provide a current, signed curriculum vitae and a completed Form 1572.  The 
Investigator shall promptly update this information if any relevant changes occur in the course of the 
study or for one year following completion of the study. 
9.5.3 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of national and 
international government regulatory agency bodies have access to original source documentation to 
ensure data integrity. “Original” in this context is defined as the first documentation of an observation and 
does not differentiate between hard copy and electronic records.  
9.5.4 
 Retention of Study Documents 
Study-related records must be retained for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region, or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product. These documents should be retained for a longer period, however, if required 
by applicable regulatory requirements or by an agreement with the sponsor. 
The Investigator must not destroy any study-related records without receiving approval from the Sponsor. 
The Investigator must notify the Sponsor in the event of accidental loss or destruction of any study 
records. If the Investigator leaves the institution where the study was conducted, the Sponsor must be 
contacted to arrange alternative record storage options. 

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10 ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with current US FDA regulations, ICH GCP guidelines, the 
principles of the Declaration of Helsinki, and local ethical and legal requirements. 
10.1 Informed Consents and Pediatric Assents 
There are 2 Informed Consent Forms (ICFs) that may be provided to each site: one molecular screening 
ICF and one clinical study ICF.  Some sites may combine these into one ICF.  
For each type of ICF, sample ICFs will be provided to each site.  No major deviations may be made from 
the sample ICFs.  The Sponsor or designee will review the draft ICFs before they are finalized, and the 
final IRB-approved documents must be provided to the Sponsor for regulatory purposes.  If the ICFs omit 
the template provisions authorizing the Sponsor and its representatives and designees to have access to 
study participant-identifiable health information in accordance with 45 CFR Part 164, a separate written 
authorization complying with 45 CFR Part 164 must be prepared for review and approval by the Sponsor 
before use. 
The ICFs must be signed by the patient or the patient’s legal guardian before his or her participation in the 
study, including prior to any study-specific activities or procedures.  A copy of each ICF must be 
provided to the patient or the patient's legal guardian.  If necessary, the ICFs will be provided in a 
certified translation of the local language. 
Pediatric assent may also be required, according to local laws and regulations, in order for an adolescen to 
enroll in a cohort for which adolescents are eligible.   
Signed consent forms and, where applicable, assent forms, must remain in each patient’s study file and 
must be available for verification by study monitors or authorized regulatory representatives at any time. 
10.2 Institutional Review Board 
This protocol, the ICFs, relevant supporting information and all types of patient recruitment or 
advertisement information must be submitted to the IRB for review and must be approved before the 
study is initiated.  Any amendments to the protocol must also be approved by the IRB prior to 
implementing changes in the study. 
The Investigator is responsible for keeping the IRB apprised of the progress of the study and of any 
changes made to the protocol, minimally on an annual basis.  The Investigator must also keep the IRB 
informed of any significant AEs. 
10.3 Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and disclosure to third 
parties other than those noted below is prohibited.  Information obtained during the conduct of this study 
will be collected, processed, and transmitted to or for the benefit of the Sponsor in accordance with 
applicable law, as discussed below. Information contained therein will be maintained in accordance with 
applicable law protecting patient privacy and may be inspected by the clinical researcher, the researcher’s 
staff, the Sponsor and its representatives, to check, process, evaluate, and use the information collected 
during the study.  Processing, evaluation or use of the information will be performed by a health 
professional for medical purposes and/or by those operating under a duty of confidentiality that is 
equivalent to that of a health professional.  

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Information will be transmitted and processed as the Sponsor may direct, including to the Sponsor and its 
representatives in the United States or elsewhere. Information obtained from the study will be used by the 
Sponsor in connection with the development of the study drug, including possible filing of applications 
with governmental authorities for marketing approval and for other pharmaceutical and medical research 
purposes. The Study Investigator is obliged to provide the Sponsor with complete test results and all data 
developed in this study and, in this regard, will obtain all necessary patient or other authorizations.  This 
information may be disclosed to other physicians who are conducting similar studies and to the 
FDA/applicable regulatory agencies as deemed necessary by the Sponsor.  Patient-specific information 
may be provided to other appropriate medical personnel only with the patient’s permission or as required 
or permitted by applicable law. 
All Investigators and research study personnel who process information from the study must agree to take 
appropriate measures to prevent unauthorized or unlawful processing or disclosure of data.  To ensure 
compliance with current Federal Regulations and the ICH GCP guidelines, data generated by this study 
must be available for inspection upon request by representatives of the FDA, national and local health 
authorities, the Sponsor and the IRB for each study site. 
The Sponsor intends to pursue publication of the results of the study in cooperation with the Investigators, 
subject to the terms and conditions of the clinical trial agreement between the Sponsor and Investigators.  
Sponsor approval is required for publication of any data subsets. Final authorship will be determined at 
least in part based on the number of qualified patients enrolled by each center.  Patient names and other 
personal data relating to an identified or identifiable patient (such as photographs, audio, videotapes or 
other factors specific to physical, physiological, mental, economic, cultural or social identity) may not be 
disclosed in any publication without prior written authorization from the Sponsor and the patient. 
 

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11 ADMINISTRATIVE STRUCTURE OF THE STUDY 
The Sponsor or its designated representative will be responsible for data management, data summary 
and/or analysis, and preparation of a clinical study report.  
Clinical laboratory parameters (hematology, serum chemistry, coagulation, urinalysis, pregnancy test, 
tumor markers) will be assessed by local laboratories and results recorded by the site staff on the 
appropriate eCRF pages. 
Laboratory-based pharmacodynamic and pharmacokinetics assessments will be conducted at a central 
laboratory designated by the Sponsor, unless such assessments are specifically allowed to be performed 
by local laboratories with appropriate capabilities.   

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12 REFERENCES 
 1 Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011). Translating p53 into the clinic. Nature 
Reviews Clinical Oncology, 8(1), 25-37. 
2 Vogelstein, B., Lane, D., & Levine, A. J. (2000). Surfing the p53 network. Nature, 408(6810), 307-310. 
3 Bernal, F., Wade, M., Godes, M., Davis, T. N., Whitehead, D. G., Kung, A. L., & Walensky, L. D. 
(2010). A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell, 18(5), 411-
422. 
4 Marine, J. C. (2011). MDM2 and MDMX in cancer and development. Current Topics in Developmental 
Biology, 94(1), 45-75. 
5 Migliorini, D., Denchi, E. L., Danovi, D., Jochemsen, A., Capillo, M., Gobbi, A., & Marine, J. C. 
(2002). Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early 
embryonic mouse development. Molecular and Cellular Biology, 22(15), 5527-5538. 
6 Wade, M., Li, Y. C., & Wahl, G. M. (2013). MDM2, MDMX and p53 in oncogenesis and cancer 
therapy. Nature Reviews Cancer, 13(2), 83-96. 
7 Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997). Mdm2 promotes the rapid degradation of 
p53. Nature, 387(6630), 296-299. 
8 Onel, K., & Cordon-Cardo, C. (2004). MDM2 and prognosis. Molecular Cancer Research, 2(1), 1-8. 
9 Gembarska, A., Luciani, F., Fedele, C., Russell, E. A., Dewaele, M., Villar, S., & Marine, J. C. (2012). 
MDM4 is a key therapeutic target in cutaneous melanoma. Nature Medicine, 18(8), 1239-1247. 
10 Macchiarulo, A., Giacchè, N., Carotti, A., Moretti, F., & Pellicciari, R. (2011). Expanding the horizon 
of chemotherapeutic targets: From MDM2 to MDMX (MDM4). MedChemComm, 2(6), 455-465. 
11 Bird, G. H., Madani, N., Perry, A. F., Princiotto, A. M., Supko, J. G., He, X., & Walensky, L. D. 
(2010). Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide 
therapeutic. Proceedings of the National Academy of Sciences USA, 107(32), 14093-14098. 
12 Fry, D. C., Graves, B., & Vassilev, L. T. (2005). Development of E3‐Substrate (MDM2‐p53)–Binding 
Inhibitors: Structural Aspects. Methods in Enzymology, 399, 622-633. 
13 Graves, B., Thompson, T., Xia, M., Janson, C., Lukacs, C., Deo, D., & Vassilev, L. T. (2012). 
Activation 
of 
the 
p53 
pathway 
by 
small-molecule-induced 
MDM2 
and 
MDMX 
dimerization. Proceedings of the National Academy of Sciences USA, 109(29), 11788-11793. 
14 Kurzrock, R., Blay, J. Y., Nguyen, B. B., Wagner, A. J., Maki, R. G., Schwartz, G. K., & Nichols, G. L. 
(2012, May). A phase I study of MDM2 antagonist RG7112 in patients (pts) with relapsed/refractory 
solid tumors. Journal of Clinical Oncology, 30(suppl; abstr e 136000).  
15 Iancu-Rubin, C., Mosoyan, G., Glenn, K., Gordon, R. E., Nichols, G. L., & Hoffman, R. (2014). 
Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Experimental 
Hematology.42, 137-145. 

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16 Garcia, D., Warr, M. R., Martins, C. P., Swigart, L. B., Passegué, E., & Evan, G. I. (2011). Validation 
of MdmX as a therapeutic target for reactivating p53 in tumors. Genes & Development, 25(16), 1746-
1757. 
17 Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., & Jacks, T. 
(2007). Restoration of p53 function leads to tumour regression in vivo. Nature, 445(7128), 661-665. 
18 Bernal, F., Tyler, A. F., Korsmeyer, S. J., Walensky, L. D., & Verdine, G. L. (2007). Reactivation of 
the p53 tumor suppressor pathway by a stapled p53 peptide. Journal of the American Chemical 
Society, 129(9), 2456-2457. 
19 Brown, C. J., Quah, S. T., Jong, J., Goh, A. M., Chiam, P. C., Khoo, K. H., & Lane, D. P. (2012). 
Stapled peptides with improved potency and specificity that activate p53. ACS Chemical Biology, 8(3), 
506-512. 
20 Chang, Y. S., Graves, B., Guerlavais, V., Tovar, C., Packman, K., To, K. H., & Sawyer, T. K. (2013). 
Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-
dependent cancer therapy. Proceedings of the National Academy of Sciences USA, 110(36), E3445-
E3454. 
21 Wei, S.J., Joseph, T., Chee, S., Li L., Yurlova, L., Zolghadr, K., Brown, C., Lane, D., Verma, C., 
Ghadessy, F. (2013). Inhibition of Nutlin-Resistant HDM2 Mutants by Stapled Peptides. PLoS ONE, 
8(11):e81068. 
22. Hu, B., Gilkes, D.M., Farooqi, B., Sebti, S.M., Chen, J. (2006). MDMX Overexpression Prevents p53 
Activation by the MDM2 Inhibitor Nutlin. Journal of Biological Chemistry, 281(44):33030-33035. 
23. Bernal, F., Wade, M., Godes, M., Davis, T.N., Whitehead, D.G., Kung, A.L., Wahl, G.M., Walensky, 
L.D. (2010). A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53. Cancer Cell, 18, 
411-422. 
24 Wei, S.J., Joseph, T., Sim, A.Y.L., Yurlova, L., Zoghadr, K., Lane, D., Verma, C., Ghadessy, F. (2013). 
In Vitro Selection of Mutant HDM2 Resistant to Nutlin Inhibition. PLoS ONE, 8(4):e62564. 
25. Lønning, P.E, Knappskog, S. (2013). Mapping genetic alterations causing chemoresistance in cancer: 
Identifying the roads by tracking the drivers. Oncogene. Nov 14;32(46):5315-30. 
26 Van Tine, B.A., (2016). Multiple molecular subtypes of sarcoma allow for orphan drug development. 
The Journal of Targeted Therapies in Cancer, October, 2016. 
http://www.targetedonc.com/publications/targeted-therapies-cancer/2016/2016-october/multiple-
molecular-subtypesof-sarcoma-allow-for-orphan-drug-development?p=2 
27 Ibrance [package insert]. New York, NY: Pfizer Labs, Division of Pfizer, Inc.; 2018. 
28 Chang, Y.S., Graves, B., Guerlavais, V., Tovar, C., Packman, K., To, K-H, et al. (2013) Stapled α-
helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent 
cancer therapy. Proc Natl Acad Sci USA, 110(36), E3445-54. 
29 Deeken, J.F., Loscher, W. (2007). The blood-brain barrier and cancer: transporters, treatment, and 
Trojan horses. Clinical Cancer Research, 13(6), 1663-1674. 

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30 Dean, J.L., Thangavel, C., McClendon, A.K., Reedand, C.A., Knudsen, E.S. (2010) Therapeutic 
CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene, 29, 4018–4032. 
31 Seymour, L., Bogaerts, J., Perrone, A., Ford, R., Schwartz, L.H., Mandrekar, S., et al. (2017). 
iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol, 
18(3), e143-e152. DOI: https://doi.org/10.1016/S1470-2045(17)30074-8 
32 Muñoz-Fontela, C., Mandinova A., Aaronson, S.A., Lee, S.W. (2016). Emerging roles of p53 and other 
tumour-suppressor genes in immune regulation.  Nature Reviews Immunology, 16, 741–750.  
 

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APPENDIX A: Assessment of Performance Status - ECOG 
 
ECOG 
Performance Status* 
Criteria 
Karnofsky Score 
0 
Fully active; able to carry on all  
pre-disease performance without 
restriction 
90-100% 
1 
Restricted in physically strenuous activity 
but ambulatory 
70-80% 
2 
Ambulatory and capable of self-care, but 
unable to carry out any work activities 
50-60% 
3 
Capable of only limited self-care; 
confined to bed or chair more than 50% 
of waking hours 
30-40% 
4 
Completely disabled 
10-20% 
* Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group.  Am J 
Clin Oncol 5:649-655, 1982. 
 

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APPENDIX B: Marketed Drug Products with a Predominant Hepatobiliary Transporter Clearance 
Mechanism; Marketed Drug Products that May Cause CYP3A-mediated Drug-drug Interactions 
with Palbociclib 
Marketed Drug Products with a Predominant Hepatobiliary Transporter Clearance Mechanism 
Because of in vitro findings of transporter enzyme inhibition (e.g., OATP1B1, OATP1B3, BSEP) at 
concentrations that may be clinically relevant (e.g., at Cmax of high-dose levels of ALRN-6924), the 
possibility of drug-drug interactions of ALRN-6924 with medications that are predominantly cleared by 
hepatobiliary transporters should be considered.  In particular, methotrexate and statins (e.g., atorvastatin, 
rosuvastatin) should not be dosed on the day of the ALRN-6924 infusion and within 48 hours after an 
ALRN-6924 infusion. Additional medications that may be affected by co-administration with ALRN-
6924 are listed below, however, this list may not be all inclusive and the investigator should consult with 
a pharmacist, or other professional resource, to identify other medications that may be cleared in this 
manner. The Sponsor’s Medical Monitor should be contacted if there are questions regarding the 
concomitant use of drugs with a predominantly hepatobiliary transporter clearance mechanism. Table is 
not meant to be fully comprehensive and inclusive of all medications.  
 
Asunaprevir 
Atorvastatin 
Bosentan 
Caspofungin 
Cerivastatin 
Danoprevir 
Eluxadoline 
Eprosartan 
Fexafenadine 
Fimasartan 
Fluvastatin 
Grazoprevir 
Irbesartan 
Lovastatin 
Losartan 
Methotrexate 
Olmesartan 
Pravastatin 
Repaglinide 
Rifampin 
Rosuvastatin 
Simvastatin 
Simiprevir 
Tacrolimus 
Telmisartan 
Thyroxine 
Valsartan 
Velpatasvir 
Voxilsprevir 
 
 

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Marketed Drug Products that May Cause CYP3A-mediated Drug-drug Interactions with Palbociclib 
Note: The following is not an exhaustive list.  Please check for the potential liability of the drug to be co-
administered drug for CYP3A-mediated drug-drug interaction before use. 
Strong CYP3A Inhibitors1 
Clarithromycin 
Indinavir 
Itraconazole 
Ketoconazole 
lopinavir/ritonavir 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Voriconazole 
Also avoid – Grape fruit and Grapefruit Juice 
Strong CYP3A Inducers2 
Phenytoin 
Rifampin 
Carbamazepine 
Enzalutamide 
St John’s Wort 
Sensitive CYP3A Substrates3 
Alfentanil 
Cyclosporine 
Dihydroergotamine 
Ergotamine 
Everolimus 
Fentanyl 
Pimozide 
Quinidine 
Sirolimus 
Tacrolimus 
1 Avoid concomitant use of strong CYP3A inhibitors. If co-administration of palbociclib with a strong CYP3A 
inhibitor cannot be avoided, reduce the dose of palbociclib. 
2 Avoid concomitant use of strong CYP3A inducers. 
3 The dose of the sensitive CYP3A substrate with a narrow therapeutic index may need to be reduced as palbociclib 
may increase their exposure. 

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APPENDIX C:  Dose Regimen A and A-2 - Study Activities Through Cycle 1 - ALRN single agent therapy 
 
 
Molecular 
Screen 
Clinical 
Screen 
-21 days 
Within 7 
days prior 
to Day 1 
Day 1 
Day 2 
Day 3 
DEP 
only 
Day 8 
EXP: ± 1 d 
Day 15 
EXP: ± 1 d 
Day 16  
Day 
2215 
±1 d 
 
 
 
 
Pre- 
Dose 
Post- 
Dose 
 
 
Pre- 
Dose 
Post- 
Dose 
Pre- 
Dose 
Post- 
Dose 
 
 
Written informed consent 
See 6.2 
See 6.2 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy or archive tissue sample 
See 3.21 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Blood test for HIV, hepatitis B and C 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HPV test3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test 
 
 
Within 2 
days prior 
to Day 1 
 
 
 
 
 
 
 
 
 
 
Vital signs4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam5 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
12-lead ECG6 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Laboratory assessments – chemistry 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
 
Laboratory assessments – hematology 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Laboratory assessments - coagulation 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
 
Laboratory assessments - urinalysis 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
 
Laboratory assessments – lymphocyte subset 
testing 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Laboratory assessments – CRP, fibrinogen 
 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
Laboratory assessments – reticulocytes 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood Collection – immunogenicity 
 
 
 
X7 
 
 
 
 
 
 
 
 
 
Blood Collection - PD assessments-MIC-1 
 
 
 
X7 
X7 
X8 
X9 
 
 
 
 
 
 
Blood Collection - PD assessments-CTC 
DEP and select sites in EXP 
 
 
 
X7 
X7 
X8 
 
 
 
 
 
 
 
Blood Collection - PK assessments 
 
 
 
X7 
X7 
X8 
X9 
 
 
 
 
 
 
Blood Collection –cell-free DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 

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Molecular 
Screen 
Clinical 
Screen 
-21 days 
Within 7 
days prior 
to Day 1 
Day 1 
Day 2 
Day 3 
DEP 
only 
Day 8 
EXP: ± 1 d 
Day 15 
EXP: ± 1 d 
Day 16  
Day 
2215 
±1 d 
Germline DNA sample10 
 
 
 
X 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
Biopsy for biomarker assessments /p53 status 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
Tumor Assessment/Imaging11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ALRN-6924 dosing12 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Concomitant medications13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment14 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEP: For Days 1 through 16, no pre-specified visit windows exist to ensure timely safety follow-up and PK/PD sampling.  However, at the Investigator’s discretion, it may be necessary to conduct a 
study visit on an alternative day than described in this schedule in order to protect the safety, rights, or welfare of the patient.  If this is the situation, the Investigator will confer with and obtain 
approval from the Medical Monitor. 
1 A pre-treatment biopsy or archival sample is required for p53 testing. For patients with a study biopsy performed immediately prior to enrollment, optional needle biopsy to be performed within 24 
hours of Cycle 1 Day 15 infusion OR Cycle 2 Day 15 infusion. Decision to be made at the discretion of the Investigator. In EXP, optional biopsies include pre-treatment, during treatment, and one or 
more at times of suspected and/or confirmed progression.  
2 Can be omitted if screening laboratory assessments are performed within 7 days of the first dose of ALRN-6924. Screening/within 7 day assessments are to be used for eligibility assessment.  
3 HPV status must be determined for tumors that are associated with HPV infection, including (but not limited to) cervical cancers, oropharyngeal cancer, head and neck squamous cell cancers or anal 
cancer, unless HPV status of the tumor is already known and documented.   
4 Blood pressure, pulse, respiration rate, body temperature.   
  Cycle 1, Days 1, 8, 15: On the days of drug administration vital signs will be recorded pre-dose (within 30 minutes prior to SOI) and at the following timepoints:  
During infusion:  
DR-A (one hour infusion): 15 min (± 3 min) and 30 min (± 3 min) 
DR-A-2 (two hour infusion): 30 min (± 3 min) and 60 min (± 3 min)  
Post-infusion: At EOI (±5 min), 1 hr (±5 min) and 2 hr (±10 min), 4 hrs (±10 min) following EOI. On Cycle 1 Day 1 additional timepoints include 6 hrs (±10 min) and 8 hrs (±10 min) 
following EOI. Additional vital signs will be collected at the discretion of the investigator. 
5 Full physical examination to be performed at Screening, Day 1 Predose, and End of Treatment; all other physical examinations may be symptom directed. Height and weight to be collected on Day 1. 
6 ECGs to be performed after the patient has been supine for at least 10 minutes.  Readings should be performed with the patient in the same physical position.  Screening and pre-dose ECG recording 
should be taken in triplicate with 5-10 minutes between readings.  Thereafter, subsequent readings on that same day will be performed in triplicate only if patient has a QTc that is a) >500 msec; b) 
increased by 60 msec over pre-dose; or c) decreased by 50 msec below pre-dose value.  Timepoints on Cycle 1, Day 1: Pre-dose (within 30 minutes prior to infusion), end of infusion (EOI +5 min) and 
at 1 (± 5 min) and 2 hr (±10 min) after EOI.  
7 PD (MIC-1 and CTC): Within 1 hour before the start of infusion (SOI), and 4 (±10 min) and 8 hours (±2 hours) after EOI. 
    PK: Within 1 hour before SOI; at EOI (+5 min) and at 30 min (±5 min), 1 hour (±5 min), 2 (±10 min), 4 (±10 min) and 8 hours (±2 hours) after EOI. 
    Immunogenicity: Within 1 hour before the SOI on Day 1. 
 Patients who are already enrolled in the expansion and consent to this PD/PK testing will have blood drawn at their next available cycle (i.e. if the next available cycle is Cycle 4, they will follow the 
PK/PD Cycle 1 testing at Cycle 4, and will follow the indicated Cycle 2 testing at Cycle 5). 

Protocol ALRN-6924-1-01 
 
 
 
 
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8 PD (CTC and MIC-1) and PK: blood should be collected 24 hours (±4 h) after the initiation of Day 1 infusion. 
9 DEP only: PD (MIC-1 only) and PK: blood should be collected 48 hours (±4 h) after the initiation of Day 1 infusion.  
10In patients consenting to optional biopsies, buccal swab for germline DNA (EXP only) 
11 RECIST 1.1- (for solid tumor patients) or IWG 2014- (for lymphoma patients) compliant imaging for disease assessment and tumor measurements as well as laboratory-based assays (e.g., prostate 
specific antigen) for patients with relevant disease indications.  
12 During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. In dosing regimen DR-A, ALRN-6924 will be infused over 1 hour 
(±15 min). In dosing regimen DR-A-2, ALRN-6924 will be infused over 2 hours (±15 min), with dexamethasone (4 mg orally or IV) administered 4 hours after the end of infusion to mitigate potential 
infusion reactions. At the end of the infusion for both DR-A and DR-A-2, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated.   
13 All concomitant medications taken within 28 days of beginning the study (Cycle 1 Day 1) until 30 days after last infusion or start of subsequent therapy must be reported in the relevant eCRF pages, 
including supportive care drugs and drugs used for treatment of AEs or chronic diseases. 
14 AE reporting begins at the point of the first ALRN-6924 infusion until 30 days after last infusion or start of subsequent therapy; until all drug-related toxicities and ongoing SAEs have resolved, 
whichever is later; or until the Investigator assesses AEs as “chronic” or “stable.” 
15This visit will be performed for all patients in DEP and performed in EXP only if the patient has experienced any grade 3 neutropenia, anemia or thrombocytopenia while on study, regardless of the 
relationship to ALRN-6924 
 

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APPENDIX D: Dose Regimen A and A-2 -  Study Activities Cycle 2 and Beyond - ALRN single agent therapy 
 
 
Day 11 
±3 d 
Day 8 
±1 d 
Day 15 
±1 d 
Day 168 
±2 d 
At the end 
of cycles 2, 
4, 6, etc. 
End-of-Treatment 
30 + 5 d after last dose 
or at study withdrawal 
Long-Term 
Follow Up 
(EXP only)16 
 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
 
 
 
 
Serum or urine pregnancy 
 
 
 
 
 
 
 
 
X 
 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Physical exam3 
X 
 
X 
 
X 
 
 
 
X 
 
12-lead ECG4 
X 
X 
 
 
 
 
 
 
X 
 
Laboratory assessments – chemistry5 
X 
 
 
 
X 
 
X 
 
X 
 
Laboratory assessments – hematology5 
X 
 
X 
 
X 
 
X 
 
X 
 
Laboratory assessments – coagulation5 
X 
 
 
 
X 
 
X 
 
X 
 
Laboratory assessments – urinalysis5 
X 
 
 
 
X 
 
X 
 
X 
 
Laboratory assessments – CRP, fibrinogen 
Cycle 2 
only 
 
 
 
Cycle 2 
only 
 
Cycle 2 
only 
 
 
 
Collection of blood for immunogenicity6 
Cycle 2, 
3, 5 only 
 
 
 
 
 
 
 
X 
 
Blood Collection - PK assessments  
 
 
 
 
Cycle 2 
only7 
Cycle 2 
only7 
Cycle 2: 
DEP 
only7 
 
 
 
Blood Collection - cell-free DNA6 
Cycle 5 
only 
 
 
 
 
 
 
 
X 
 
ECOG Performance status9 
X 
 
X 
 
X 
 
 
 
X 
 
Biopsy for biomarker assessments /p53 status10 
 
 
 
 
 
 
X 
 
X 
 
Tumor Assessment/Imaging11 
 
 
 
 
 
 
 
X 
X12 
 
ALRN-6924 dosing13 
X 
 
X 
 
X 
 
 
 
 
 
Concomitant medications14 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
AE assessment15 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Phone calls or other contact 
 
 
 
 
 
 
 
 
 
X 
1 “Day 29” = Day 1 of next cycle for patients continuing treatment.  Day 1 pre-dose evaluations for Cycle 2 and subsequent cycles are to be done within 3 days prior to next cycle drug administration. 
2 Blood pressure, pulse, respiration rate, body temperature. For patients on > 1 year, this procedure is no longer a mandatory study procedure:  

Protocol ALRN-6924-1-01 
 
 
 
 
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On the days of drug administration (Days 1, 8, 15 of each cycle) vital signs will be recorded pre-dose (within 30 minutes prior to SOI) and at the following timepoints:  
During infusion: 
DR-A (one hour infusion): 15 min (± 3 min) and 30 min (± 3 min) 
DR-A-2 (two hour infusion): 30 min (± 3 min) and 60 min (± 3 min).  
Post-infusion: At EOI (±5 min) and as clinically indicated following EOI. In cycle 2 only, vital signs will be collected at 1 hr (±5 min), 2 hrs (±10 min) and 4 hrs (±10 min) following EOI. Additional 
vital signs will be collected at the discretion of the investigator.  
3 Full physical examination to be performed at End of Treatment visit; all other physical examinations may be symptom directed. For patients on > 1 year, this procedure is no longer a mandatory study 
procedure. Weight to be collected at Day 1 (+/- 3 days) of each cycle. 
4 ECGs to be performed after the patient has been supine for at least 10 minutes.  Readings should be performed with the patient in the same physical position.  Pre-dose ECG recording should be taken in 
triplicate with 5-10 minutes between readings.  Thereafter, subsequent readings on that same day will be performed in triplicate only if patient has a QTc that is a) >500 msec; b) increased by 60 msec 
over pre-dose; or c) decreased by 50 msec below pre-dose value.   Timepoints on Day 1 of new cycle: At pre-dose (within 30 minutes prior to infusion) and EOI (+5 min). For patients on > 1 year, this 
procedure is no longer a mandatory study procedure. 
5 For patients on > 1 year, the required labs are: full labs to be collected on Day 1, and hematology only at Day 15 
6 Within 1 hour before SOI 
7 PK (Cycle 2 only): Day 15-collect at EOI (+5 min) and at 1 hour (±5 min) and 4 hours (±10 min) after the end of infusion. Patients who are already enrolled in the expansion and consent to this PD/PK 
testing will have blood drawn at their next available cycle (i.e. if the next available cycle is Cycle 4, they will follow the PK/PD Cycle 1 testing at Cycle 4, and will follow the indicated Cycle 2 testing at 
Cycle 5). 
   PK (Cycle 2 only): DEP only - Day 16 - Blood should be collected 24 hours (±4 h) after the initiation of Day 15 infusion. 
8 Day 16 visit should only be completed for Cycle 2; this visit to be completed in DEP and only in EXP if the optional biopsy is performed  
9 For patients on > 1 year, this is no longer a mandatory study procedure 
10 Cycle 2 biopsy not performed if collected in specified timepoint in Cycle 1. For patients with a study biopsy performed immediately prior to enrollment, optional needle biopsy to be performed within 
24 hours of Cycle 1 Day 15 infusion OR Cycle 2 Day 15 infusion; decision to be made at the discretion of the Investigator. In EXP, optional biopsies include pre-treatment, during treatment, and one or 
more at times of suspected and/or confirmed progression.  
11 To be performed at end of even-numbered cycles (Cycle 2, Cycle 4, Cycle 6, etc.) prior to start of the next treatment cycle.  RECIST 1.1 (APPENDIX K)  measurements for patients with solid tumors; 
IWG 2014 (APPENDIX L)  measurements for patients with lymphoma. In DEP, after 1 year, assessments will be obtained at approximately 3 month intervals. After 2 years, assessments will be obtained 
at approximately 4 month intervals or per standard of care. In EXP, the frequency of imaging will not change after 1 year of treatment. 
12 Same method used as baseline. Perform only if no tumor assessment was performed within 6-8 weeks prior. 
13 During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. In dosing regimen DR-A, ALRN-6924 will be infused over 1 hour 
(±15 min). In dosing regimen DR-A-2, ALRN-6924 will be infused over 2 hours (±15 min), with dexamethasone (4 mg orally or IV) administered 4 hours after the end of infusion to mitigate potential 
infusion reactions. At the end of the infusion for both DR-A and DR-A-2, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated. 
14 All concomitant medications taken within 28 days of beginning the study (Cycle 1 Day 1) until 30 days after last infusion or start of subsequent therapy must be reported in the relevant eCRF pages, 
including supportive care drugs and drugs used for treatment of AEs or chronic diseases. 
15 AE reporting begins at the point of the first ALRN-6924 infusion and continues until 30 days after last infusion or start of subsequent therapy; until all drug-related toxicities and ongoing SAEs have 
resolved, whichever is later; or until the Investigator assesses AEs as “chronic” or “stable.” 
16 EXP only: Phone calls or other contact should be made approximately every 2 months following end of treatment visit to assess survival status and collect information on subsequent therapies  
 

Protocol ALRN-6924-1-01 
 
 
 
 
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APPENDIX E:  Dose Regimen B - Study Activities Through Cycle 1 
 
 
 
Molecular 
Screen 
Clinical 
Screen 
-21 days 
Within 7 
days 
prior to 
Day 1 
Day 1 
Day 2 
 
Day 
39 
 
Days  
4 and 8 
EXP: ± 1 d 
Day 11 
EXP: ± 1 d 
Day 12 
DEP only 
Day 15 
± 1 d 
EXP only 
Day 18 
± 1 d 
DEP only 
 
 
 
 
Pre- 
Dose 
Post- 
Dose 
 
 
Pre- 
Dose 
Post- 
Dose 
Pre- 
Dose 
Post- 
Dose 
 
 
 
Written informed consent 
See 6.2 
See 6.2 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy or archive tissue sample 
See 3.21 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood test for HIV, hepatitis B and C 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HPV test 3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test 
 
 
Within 2 
days prior 
to Day 1 
 
 
 
 
 
 
 
 
 
 
 
Vital signs4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam5 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
12-lead ECG6 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
Laboratory assessments – chemistry 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
Laboratory assessments – hematology 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
Laboratory assessments - coagulation 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
Laboratory assessments - urinalysis 
 
X 
X2 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
Laboratory assessments – lymphocyte subset 
testing 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Laboratory assessments – CRP, fibrinogen 
 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
Laboratory assessments – reticulocytes 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood Collection - immunogenicity 
 
 
 
X7 
 
 
 
 
 
 
 
 
 
 
Blood Collection - PD assessments-MIC-1 
 
 
 
X7 
X7 
X8 
X9 
X9 
 
 
 
 
 
 
Blood Collection - PD assessments-CTC 
DEP and select sites in EXP 
 
 
 
X7 
X7 
X8 
 
 
 
 
 
 
 
 
Blood Collection - PK assessments 
 
 
 
X7 
X7 
X8 
X9 
X9 
 
 
 
 
 
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 106 of 135 
Confidential 
 
 
Molecular 
Screen 
Clinical 
Screen 
-21 days 
Within 7 
days 
prior to 
Day 1 
Day 1 
Day 2 
 
Day 
39 
 
Days  
4 and 8 
EXP: ± 1 d 
Day 11 
EXP: ± 1 d 
Day 12 
DEP only 
Day 15 
± 1 d 
EXP only 
Day 18 
± 1 d 
DEP only 
Blood Collection – cell-free DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Germline DNA sample10 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Biopsy for biomarker assessments/p53 status  
 
 
 
 
 
 
EXP: 
Day 3 
or 101 
 
 
 
 
DEP: X1 
 
 
Tumor Assessment/Imaging11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ALRN-6924 dosing12 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Concomitant medications13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment14 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEP: For Days 1 through 12, no pre-specified visit windows exist to ensure timely safety follow-up and PK/PD sampling.  However, at the Investigator’s discretion, it may be necessary to conduct a 
study visit on an alternative day than described in this schedule in order to protect the safety, rights, or welfare of the patient.  If this is the situation, the Investigator will confer with and obtain 
approval from the Medical Monitor. 
1 A pre-treatment biopsy or archival sample is required for p53 testing. For patients with a study biopsy performed immediately prior to enrollment, optional needle biopsy to be performed within 24 
(DEP) or 48 (EXP) hours of Cycle 1 Day 11 infusion OR Cycle 2 Day 11 infusion. In EXP, optional biopsies include pre-treatment, during treatment, and one or more at times of suspected and/or 
confirmed progression. 
2 Can be omitted if screening laboratory assessments are performed within 7 days of the first dose of ALRN-6924. Screening/within 7 day assessments are to be used for eligibility assessment. 
3 HPV status must be determined for tumors that are associated with HPV infection, including (but not limited to) cervical cancers, oropharyngeal cancer, head and neck squamous cell cancers or anal 
cancer, unless HPV status of the tumor is already known and documented.   
4 Blood pressure, pulse, respiration rate, body temperature.   
  Cycle 1, Days 1, 4, 8, 11: On the days of drug administration vital signs will be recorded pre-dose (within 30 minutes prior to SOI) and at the following timepoints:  
During infusion: 15 min (± 3 min) and 30 min (± 3 min) 
Post-infusion: At EOI (±5 min), 1 (±5 min), 2 hrs (±10 min) and 4 hrs (±10 min) following EOI. On Cycle 1 Day 1 additional timepoints include 6 hrs (±10 min) and 8 hrs (±10 min) 
following EOI. Additional vital signs will be collected at the discretion of the investigator. 
5 Full physical examination to be performed at Screening, Day 1 Predose and End of Treatment; all other physical examinations may be symptom directed. Weight to be collected at Day 1. 
6 ECGs to be performed after the patient has been supine for at least 10 minutes.  Readings should be performed with the patient in the same physical position.  Screening and pre-dose ECG recording 
should be taken in triplicate with 5-10 minutes between readings.  Thereafter, subsequent readings on that same day will be performed in triplicate only if patient has a QTc that is a) >500 msec; b) 
increased by 60 msec over pre-dose; or c) decreased by 50 msec below pre-dose value.  Timepoints on Cycle 1, Day 1: Pre-dose (within 30 minutes prior to infusion), end of infusion (EOI +5 min) and 
at 1 (±5 min) and 2 hours (±10 min) after EOI.  
7 PD (MIC-1 and CTC): within 1 hour before the start of infusion (SOI) and 4 (± 10 min) and 8 hr (± 2 hours) after EOI. 
    PK: Within 1 hour before SOI; at EOI (+5 min) and at 30 min (± 5 min), 1 hour (±5 min), 2 (± 10 min), 4 (± 10 min) and 8 hours (±2 hours ) after EOI. 
    Immunogenicity: Within 1 hour before the SOI on Day 1. 
8 PD (CTC and MIC-1) and PK: Day 2: Collect blood samples 24 hours (±4 h) after the initiation of Day 1 infusion. 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 107 of 135 
Confidential 
9 PD (MIC-1 only) and PK: Day 3 (Day 3 for DEP only):  Collect blood samples 48 hours (±4 h) after the initiation of Day 1 infusion. Day 4: Collect blood samples within 1 hour prior to SOI. Visit to 
be completed in EXP only if biopsy performed. In EXP, PK and PD not collected at this visit.  
10 In patients consenting to optional biopsies, buccal swab for germline DNA (EXP only) 
11 RECIST 1.1 - (for solid tumor patients) or IWG 2014- (for lymphoma patients) compliant imaging for disease assessment and tumor measurements as well as laboratory-based assays (e.g., prostate 
specific antigen) for patients with relevant disease indications. 
12 During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. ALRN-6924 will be infused over 1 hour (±15 min). At the end of 
the infusion, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated. 
13 All concomitant medications taken within 28 days of beginning the study (Cycle 1 Day 1) until 30 days after last infusion or start of subsequent therapy must be reported in the relevant eCRF pages, 
including supportive care drugs and drugs used for treatment of AEs or chronic diseases. 
14 AE reporting begins at the point of the first ALRN-6924 infusion and continues until 30 days after last infusion or start of subsequent therapy; until all drug-related toxicities and ongoing SAEs have 
resolved, whichever is later; or until the Investigator assesses AEs as “chronic” or “stable.” 
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 108 of 135 
Confidential 
APPENDIX F:  Dose Regimen B - Study Activities Cycle 2 and Beyond 
 
 
Day 11 
±3 d 
Day 3  
EXP 
only 9 
 
Day 4 and 8 
±1 d 
 
 
Day 11 
±1 d 
 
Day 
1215 
DEP 
only 
Day 
1516 
EXP 
only 
After last 
dose in 
cycles 3, 6, 
9 etc. 
End-of-
Treatment 
30 + 5 d after last 
dose or at study 
withdrawal  
Long-
Term  
Follow 
Up 17 
(EXP 
only) 
 
Pre-
dose 
Post-
dose 
 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
 
 
 
 
 
Serum or urine pregnancy 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs2 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Physical exam3 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
12-lead ECG4 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments – chemistry5 
X 
 
 
 
 
Starting 
at Cycle 
4 
 
X 
X 
 
X 
 
Laboratory assessments – 
hematology5 
X 
 
 
X 
 
Starting 
at Cycle 
4 
 
X 
X 
 
X 
 
Laboratory assessments – 
coagulation5 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Laboratory assessments – urinalysis5 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Laboratory assessments – CRP, 
fibrinogen 
Cycle 2 
only 
 
 
 
 
Cycle 2 
only 
 
Cycle 2 
only 
 
 
 
 
Collection of blood for 
immunogenicity6 
Cycle 2, 
3, 5 
only 
 
 
 
 
 
 
 
 
 
X 
 
Blood Collection - PK assessments  
 
 
 
 
 
X7 
X7 
X7 
 
 
 
 
Blood Collection- cell-free DNA6 
Cycle 5 
only 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance status8 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
Biopsy for biomarker assessments 
/p53 status 
 
 
Day 3 
or 109 
 
 
 
 
X9 
 
 
X9 
 
Tumor Assessment/Imaging 
 
 
 
 
 
 
 
 
 
 X10 
X11 
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 109 of 135 
Confidential 
 
Day 11 
±3 d 
Day 3  
EXP 
only 9 
 
Day 4 and 8 
±1 d 
 
 
Day 11 
±1 d 
 
Day 
1215 
DEP 
only 
Day 
1516 
EXP 
only 
After last 
dose in 
cycles 3, 6, 
9 etc. 
End-of-
Treatment 
30 + 5 d after last 
dose or at study 
withdrawal  
Long-
Term  
Follow 
Up 17 
(EXP 
only) 
ALRN-6924 dosing12 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Concomitant medications13 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
AE assessment14 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Phone calls or other contact 
 
 
 
 
 
 
 
 
 
 
 
X 
1 “Day 22” = Day 1 of next cycle for patients continuing treatment.  Day 1 pre-dose evaluations for Cycle 2 and subsequent cycles are to be done within 3 days prior to next cycle drug administration. 
2 Blood pressure, pulse, respiration rate, body temperature.  On the days of drug administration (Days 1, 4, 8, and 11 of each cycle) vital signs will be recorded pre-dose (within 30 minutes prior to SOI) 
and at the following timepoints:  
(During infusion) 15 min (± 3 min) and 30 min (± 3 min);  
(Post-infusion) At EOI (±5 min) and as clinically indicated following EOI. For patients on > 1 year, this procedure is no longer a mandatory study procedure. 
In cycle 2 only, vital signs will be collected at 1 hr (±5 min), 2 hrs (±10 min) and 4 hrs (±10 min) following EOI. Additional vital signs will be collected at the discretion of the investigator. 
3 Full physical examination to be performed at End of Treatment; all other physical examinations may be symptom directed. For patients on > 1 year, this procedure is no longer a mandatory study 
procedure. Weight to be collected at Day 1 (+/- 3 days) of each cycle. 
4 ECGs to be performed after the patient has been supine for at least 10 minutes.  Readings should be performed with the patient in the same physical position.  Screening and pre-dose ECG recording 
should be taken in triplicate with 5-10 minutes between readings.  Thereafter, subsequent readings on that same day will be performed in triplicate only if patient has a QTc that is a) >500 msec; b) 
increased by 60 msec over pre-dose; or c) decreased by 50 msec below pre-dose value.   Timepoints on Day 22 of prior cycle or Day 1 of new cycle: At pre-dose (within 30 minutes prior to infusion) and 
EOI (+5 min). For patients on > 1 year, this procedure is no longer a mandatory study procedure. 
5 For patients on > 1 year, the required labs are: full labs to be collected on Day 1, and hematology only at Day 11 
6 Within 1 hour before SOI  
7 PK (Cycle 2 only): Day 11 collect at EOI (+5 min) and at 1 hour (±5 min) and 4 hours (±10 min) after the end of infusion.  
   DEP only:  PK (Cycle 2 only): Day 12 visit should be conducted and blood should be collected 24 hours (±4 h) after the initiation of Day 11 infusion. 
8 For patients on > 1 year, this procedure is no longer a mandatory study procedure. 
9 Cycle 2 biopsy not performed if collected in specified timepoint in Cycle 1. For patients with a study biopsy performed immediately prior to enrollment, optional needle biopsy to be performed within 
24 hours (DEP) or 48 hours (EXP) of Cycle 1 Day 11 infusion OR Cycle 2 Day 11 infusion. In EXP, optional biopsies include pre-treatment, during treatment, and one or more at times of suspected 
and/or confirmed progression.   
10 To be performed at end of odd-numbered cycles (Cycle 3, 6, 9, etc.) prior to start of the next treatment cycle.  RECIST 1.1 (APPENDIX K) measurements for patients with solid tumors; IWG 2014 
(APPENDIX L)  measurements for patients with lymphoma. In DEP, after 1 year, assessments will be obtained at approximately 3 month intervals. After 2 years, assessments will be obtained at 
approximately 4 month intervals or per standard of care. In EXP, the frequency of imaging will not change after 1 year of treatment. 
11 Same method used as baseline. Perform only if no tumor assessment was performed within 6-8 weeks prior. 
12 During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. ALRN-6924 will be infused over 1 hour (±15 min). At the end of the 
infusion, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated. 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 110 of 135 
Confidential 
13 All concomitant medications taken within 28 days of beginning the study (Cycle 1 Day 1) until 30 days after last infusion or start of subsequent therapy must be reported in the relevant eCRF pages, 
including supportive care drugs and drugs used for treatment of AEs or chronic diseases. 
14 AE reporting begins at the point of the first ALRN-6924 infusion until 30 days after last infusion or start of subsequent therapy; until all drug-related toxicities and ongoing SAEs have resolved, 
whichever is later; or until the Investigator assesses AEs as “chronic” or “stable.” 
15 Day 12 visit should only be completed for Cycle 2 
16 Day 15 visit to be completed in Cycles 1-3 and then at the discretion of the investigator 
17 EXP only: Phone calls or other contact should be made approximately every 2 months following end of treatment visit to assess survival status and collect information on subsequent therapies  
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 111 of 135 
Confidential 
APPENDIX G:  Dose Regimen C - Study Activities Through Cycle 1  
 
 
 
Molecular 
Screen 
Clinical 
Screen 
-21 days 
Within 7 
days prior 
to Day 1 
Day 1 
Day 
215 
Days  
3 
± 1 d 
Day 5 
± 1 d 
Day 8 
± 1 d 
Day 15 
± 1 d 
 
 
 
 
Pre- 
Dose 
Post- 
Dose 
 
Pre- 
Dose 
Post- 
Dose 
Pre- 
Dose 
Post- 
Dose 
 
 
Written informed consent 
See 6.2 
See 6.2 
 
 
 
 
 
 
 
 
 
 
Medical and disease history 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy or archive tissue sample 
See 3.21 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
 
X 
X 
 
 
 
 
 
 
 
 
 
Blood test for HIV, hepatitis B and C 
 
X 
 
 
 
 
 
 
 
 
 
 
HPV test 3 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test 
 
 
Within 2 
days prior 
to Day 1 
 
 
 
 
 
 
 
 
 
Vital signs4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam5 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
12-lead ECG6 
 
X 
 
X 
X 
 
 
 
 
 
 
 
Laboratory assessments – chemistry 
 
X 
X2 
X 
 
X 
X7 
 
X7 
 
X7 
X7 
Laboratory assessments – hematology 
 
X 
X2 
X 
 
X 
X7 
 
X7 
 
X7 
X7 
Laboratory assessments - coagulation 
 
X 
X2 
X 
 
X 
 
 
 
 
 
 
Laboratory assessments - urinalysis 
 
X 
X2 
X 
 
X 
 
 
 
 
 
 
Laboratory assessments – lymphocyte subset 
testing 
 
 
X 
 
 
 
 
 
X 
 
 
 
Laboratory assessments – CRP, fibrinogen 
 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Laboratory assessments – reticulocytes 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood Collection - immunogenicity 
 
 
 
X8 
 
 
 
 
 
 
 
 
Blood Collection - PD assessments-MIC-1 
 
 
 
X8 
X8 
X9 
X10 
 
X10 
 
X10 
 
Blood Collection - PD assessments-CTC 
(select sites only) 
 
 
 
X8 
X8 
X9 
 
 
 
 
 
 
Blood Collection - PK assessments 
 
 
 
X8 
X8 
 
X10 
X10 
X10 
X10 
X10 
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 112 of 135 
Confidential 
 
 
Molecular 
Screen 
Clinical 
Screen 
-21 days 
Within 7 
days prior 
to Day 1 
Day 1 
Day 
215 
Days  
3 
± 1 d 
Day 5 
± 1 d 
Day 8 
± 1 d 
Day 15 
± 1 d 
Blood Collection – cell-free DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
Germline DNA sample11 
 
 
 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
Biopsy for biomarker assessments/p53 status 
 
 
 
 
 
Day 2 
or 41 
 
 
 
 
 
 
Tumor Assessment/Imaging12 
 
X 
 
 
 
 
 
 
 
 
 
 
ALRN-6924 dosing13 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Concomitant medications14 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE assessment15 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
1 For patients with a study biopsy performed immediately prior to enrollment, needle biopsy to be performed within 24 hours after Day 1 infusion OR Day 3 infusion; decision to be made at the 
discretion of the Investigator and only for patients with a study biopsy prior to their study participation. A pre-treatment biopsy or archival sample is required for p53 testing. For patients with a study 
biopsy performed immediately prior to enrollment, optional needle biopsy to be performed within 24 hours of Cycle 1 Day 1 infusion OR Day 3 infusion. Biopsy may also be performed at visit 2. 
Decision to be made at the discretion of the Investigator. In EXP, optional biopsies include pre-treatment, during treatment, and one or more at times of suspected and/or confirmed progression. 
2 Can be omitted if screening laboratory assessments are performed within 7 days of the first dose of ALRN-6924. Screening/within 7 day assessments are to be used for eligibility assessment. 
3 HPV status must be determined for tumors that are associated with HPV infection, including (but not limited to) cervical cancers, oropharyngeal cancer, head and neck squamous cell cancers or anal 
cancer, unless HPV status of the tumor is already known and documented.  
4 Blood pressure, pulse, respiration rate, body temperature.   
  Cycle 1, Days 1, 3, 5: On the days of drug administration vital signs will be recorded pre-dose (within 30 minutes prior to SOI) and at the following timepoints: 
  During infusion: 15 min (± 3 min) and 30 min (± 3 min) 
  Post-infusion: At EOI (±5 min), 1 (±5 min), 2 hrs (±10 min) and 4 hrs (±10 min) following EOI. On Cycle 1 Day 1 additional timepoints include 6 hrs (±10 min) and 8 hrs (±10 min) following EOI. 
Additional vital signs will be collected at the discretion of the investigator. 
5 Full physical examination to be performed at Screening, Day 1 Predose and End of Treatment; all other physical examinations may be symptom directed. Weight to be collected at Day 1. 
6 ECGs to be performed after the patient has been supine for at least 10 minutes.  Readings should be performed with the patient in the same physical position.  Screening and pre-dose ECG recording 
should be taken in triplicate with 5-10 minutes between readings.  Thereafter, subsequent readings on that same day will be performed in triplicate only if patient has a QTc that is a) >500 msec; b) 
increased by 60 msec over pre-dose; or c) decreased by 50 msec below pre-dose value.  Timepoints on Cycle 1, Day 1: Pre-dose (within 30 minutes prior to infusion), end of infusion (EOI +5 min) and 
at 1 (±5 min) and 2 hours (±10 min) after EOI.  
7 Days 3 and 5: Perform hematology and the following chemistries: glucose, sodium, potassium, CO2, chloride, BUN [blood urea nitrogen], serum creatinine 
    Day 8 and 15: Perform hematology and clinical chemistry. 
8 PD (MIC-1 and CTC): within 1 hour before the start of infusion (SOI) and at 4 (± 10 min) and 8 hours (± 2 hours) after EOI. 
    PK: Within 1 hour before SOI; at EOI (+5 min) and at 30 min (± 5 min), 1 hour (±5 min), 2 (± 10 min), 4 (± 10 min) and 8 hours (±2 hours) after EOI. 
    Immunogenicity: Within 1 hour before the SOI on Day 1. 
9 PD (MIC-1 and CTC): Day 2: Collect blood samples 24 hours (±4 h) after the initiation of Day 1 infusion. Complete visit only if CTCs are being collected, or if optional biopsy being conducted.  
10 PD (MIC-1 only): Day 3 and 5: Collect blood samples within 1 hour prior to SOI. 
    PK Day 3: Collect blood samples within one hour prior to SOI and at EOI (±5 min) 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 113 of 135 
Confidential 
    PK Day 5: Within 1 hour before SOI; at EOI (+5 min), at 1 hour (±5 min), 2 (± 10 min) hours post EOI 
    PD (MIC-1 only) and PK: Day 8: Collect blood samples at any time 
11 In patients consenting to optional biopsies, buccal swab for germline DNA (EXP only) 
12 RECIST 1.1- (for solid tumor patients) or IWG 2014- (for lymphoma patients) compliant imaging for disease assessment and tumor measurements as well as laboratory-based assays (e.g., prostate 
specific antigen) for patients with relevant disease indications. 
13 During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. ALRN-6924 will be infused over 1 hour (±15 min). At the end of 
the infusion, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated. Patients should receive ALRN-6924 within 1 day of the scheduled dose, but 
must not receive ALRN-6924 on consecutive dosing days. 
14 All concomitant medications taken within 28 days of beginning the study (Cycle 1 Day 1) until 30 days after last infusion or start of subsequent therapy must be reported in the relevant eCRF pages, 
including supportive care drugs and drugs used for treatment of AEs or chronic diseases. 
15 AE reporting begins at the point of the first ALRN-6924 infusion until 30 days after last infusion or start of subsequent therapy; until all drug-related toxicities and ongoing SAEs have resolved, 
whichever is later; or until the Investigator assesses AEs as “chronic” or “stable. 
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 114 of 135 
Confidential 
APPENDIX H: Dose Regimen C -  Study Activities Cycle 2 and Beyond  
 
 
Day 11 
±3 d 
Day 29 
 
Day 3 
± 1 d 
 
 
Day 5 
± 1 d 
 
Day 8 
± 1 d 
 
 
Day 1515 
± 1 d 
 
 
After last 
dose in 
cycles 3, 
6, 9 etc. 
End-of-
Treatment 
30 + 5 d after 
last dose or at 
study 
withdrawal 
Long-Term 
Follow Up 16 
 
 
Pre-
dose 
Post-
dose 
 
Pre-dose 
Post-
dose 
Pre-dose 
Post-
dose 
 
 
 
 
 
Serum or urine pregnancy 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs2 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Physical exam3 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
12-lead ECG4  
X 
X 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments – chemistry5 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
Laboratory assessments – hematology5 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
Laboratory assessments – coagulation5 
X 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments – urinalysis5 
X 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments – CRP, 
fibrinogen 
Cycle 
2 only 
 
 
 
 
 
 
Cycle 2 
only 
Cycle 2 
only 
 
X 
 
Collection of blood for immunogenicity6  
Cycle 
2, 3, 5 
only 
 
 
 
 
 
 
 
 
 
X 
 
Blood Collection - PK assessments 
 
 
 
 
 
Cycle 2 
only7 
Cycle 
2 
only7 
 
 
 
 
 
Blood Collection- cell-free DNA6 
Cycle 
5 only 
 
 
 
 
 
 
 
 
 
X 
 
ECOG Performance status8 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
Biopsy for biomarker assessments /p53 
status 
 
 
Day 2 
or 49 
 
 
 
 
 
 
 
X9 
 
Tumor Assessment/Imaging 
 
 
 
 
 
 
 
 
 
X10 
X11 
 
ALRN-6924 dosing12 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Concomitant medications13 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 115 of 135 
Confidential 
 
Day 11 
±3 d 
Day 29 
 
Day 3 
± 1 d 
 
 
Day 5 
± 1 d 
 
Day 8 
± 1 d 
 
 
Day 1515 
± 1 d 
 
 
After last 
dose in 
cycles 3, 
6, 9 etc. 
End-of-
Treatment 
30 + 5 d after 
last dose or at 
study 
withdrawal 
Long-Term 
Follow Up 16 
 
AE assessment14 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Phone calls or other contact 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1 “Day 22” = Day 1 of next cycle for patients continuing treatment.  Day 1 pre-dose evaluations for Cycle 2 and subsequent cycles are to be done within 3 days prior to next cycle drug administration. 
2 Blood pressure, pulse, respiration rate, body temperature.  On the days of drug administration (Days 1, 3 and 5 of each cycle) vital signs will be recorded pre-dose (within 30 minutes prior to SOI) and at 
the following timepoints:  
(During infusion) 15 min (± 3 min) and 30 min (± 3 min);  
(Post-infusion) At EOI (±5 min) and as clinically indicated following EOI. For patients on > 1 year, this procedure is no longer a mandatory study procedure. 
In cycle 2 only, vital signs will be collected at 1 hr (±5 min), 2 hrs (±10 min) and 4 hrs (±10 min) following EOI. Additional vital signs will be collected at the discretion of the investigator. 
3 Full physical examination to be performed at End of Treatment; all other physical examinations may be symptom directed. For patients on > 1 year, this procedure is no longer a mandatory study 
procedure. Weight to be collected at Day 1 (+/- 3 days) of each cycle. 
4 ECGs to be performed after the patient has been supine for at least 10 minutes.  Readings should be performed with the patient in the same physical position.  Screening and pre-dose ECG recording 
should be taken in triplicate with 5-10 minutes between readings.  Thereafter, subsequent readings on that same day will be performed in triplicate only if patient has a QTc that is a) >500 msec; b) 
increased by 60 msec over pre-dose; or c) decreased by 50 msec below pre-dose value.   Timepoints on Day 1 of new cycle: At pre-dose (within 30 minutes prior to infusion) and EOI (+5 min). For 
patients on > 1 year, this procedure is no longer a mandatory study procedure. 
5 For patients on > 1 year, the required labs are: full labs to be collected on Day 1, and hematology only at Day 8. 
6 Within 1 hour before SOI  
7 PK (Cycle 2 only): Collect within 1 hour before SOI, at EOI (±5 min), 1 hour (±5 min), and 2 hours (±10 min) after the end of infusion. 
8 For patients on > 1 year, this procedure is no longer a mandatory study procedure. 
9 Cycle 2 biopsy not performed if collected in Cycle 1. For patients with a study biopsy performed immediately prior to enrollment, optional needle biopsy to be performed within 24 hours of Cycle 2 Day 
1 infusion OR Day 3 infusion; decision to be made at the discretion of the Investigator. Visit to be performed only if biopsy performed. In EXP, optional biopsies include pre-treatment, during treatment, 
and one or more at times of suspected and/or confirmed progression. 
10 To be performed at end of odd-numbered cycles (Cycle 3, 6, 9, etc.) prior to start of next treatment cycle.  RECIST 1.1 (APPENDIX K) measurements for patients with solid tumors; IWG 2014 
(APPENDIX L) measurements for patients with lymphoma.  In EXP, the frequency of imaging will not change after 1 year of treatment. 
11 Perform only if no tumor assessment was performed within 6-8 weeks prior. 
12 During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. ALRN-6924 will be infused over 1 hour (±15 min). At the end of the 
infusion, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated. Patients should receive ALRN-6924 within 1 day of the scheduled dose, but must 
not receive ALRN-6924 on consecutive dosing days. 
13 All concomitant medications taken within 28 days of beginning the study (Cycle 1 Day 1) until 30 days after last infusion or start of subsequent therapy must be reported in the relevant eCRF pages, 
including supportive care drugs and drugs used for treatment of AEs or chronic diseases. 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 116 of 135 
Confidential 
14 AE reporting begins at the point of the first ALRN-6924 infusion until 30 days after last infusion or start of subsequent therapy; until all drug-related toxicities and ongoing SAEs have resolved, 
whichever is later; or until the Investigator assesses AEs as “chronic” or “stable.” 
15 Day 15 visit to be completed in Cycles 1-3 and then at the discretion of the investigator. 
       16 Phone calls or other contact should be made approximately every 2 months following end of treatment visit to assess survival status and collect information on subsequent therapies  
 

Protocol ALRN-6924-1-01 
 
 
 
 
Amendment 7 – 25 Sep 2018 
 
Page 117 of 135 
Confidential 
APPENDIX I:  Combination ALRN-6924 plus Palbociclib - Study Activities Through Cycle 1 
 
 
Screening 
-21 days 
Day 1 
Day 2 
Day 8 
± 1 d 
Day 15 
± 1 d 
Day 22 
±1 d 
Procedure 
 
Pre- Dose 
Post- 
Dose 
 
Pre- Dose 
Post- Dose 
Pre- Dose 
Post- Dose 
 
Written informed consent/pediatric assent 
X 
 
 
 
 
 
 
 
 
Medical and disease history 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Tumor biopsy or archive tissue sample (NGS 
testing) 
X 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
HPV test (tumor)1 
X 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test 
X 
 
 
 
 
 
 
 
 
Vital signs2 
Within 7 days 
prior to Day 1 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam3 
X 
X 
 
 
 
 
 
 
 
12-lead ECG4 
X 
 
 
 
 
 
 
 
 
Laboratory assessments – chemistry 
Within 7 days 
prior to Day 1 
X 
 
X 
X 
 
X 
 
X 
Laboratory assessments – hematology 
Within 7 days 
prior to Day 1 
X 
 
X 
X 
 
X 
 
X 
Laboratory assessments - coagulation 
Within 7 days 
prior to Day 1 
X 
 
X 
X 
 
X 
 
X 
Laboratory assessments – reticulocytes 
 
X 
 
 
 
 
 
 
 
Blood Collection – immunogenicity 
 
Within 1 hour 
before SOI 
 
 
 
 
 
 
 
Blood Collection- cell-free DNA 
X 
 
 
 
 
 
 
 
 
Blood Collection - PK assessments  
 
X5 
X5 
X5 
X5 
X5 
ECOG Performance Status 
Within 7 days 
prior to Day 1 
X 
 
 
X 
 
X 
 
 
Tumor Assessment/Imaging 
Within 28 days 
prior to Day 1 
 
 
 
 
 
 
 
 
ALRN-6924 dosing6 
 
X 
 
X 
X 
 
Palbociclib dosing6 
 
Administered orally on Days 1 to 21 of each 28-day cycle with food 
Patient diary7 
 
Record daily during palbociclib dosing 

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Screening 
-21 days 
Day 1 
Day 2 
Day 8 
± 1 d 
Day 15 
± 1 d 
Day 22 
±1 d 
Concomitant medications 
Within 28 days prior to C1D1 until 30 days after last infusion or start of subsequent therapy 
AE assessment 
 
AE collection period begins with first dose of ALRN-6924 until 30 days post last dose or start of subsequent therapy 
 
1  HPV status must be determined only for tumors that are associated with HPV infection, including (but not limited to) cervical cancers, oropharyngeal cancer, head and neck squamous cell cancers or 
anal cancer, unless HPV status of the tumor is already known and documented.   
2  Blood pressure, pulse, respiration rate, body temperature.   
   Cycle 1, Days 1, 8, 15: On the days of drug administration vital signs will be recorded pre-dose (within 30 minutes prior to SOI) and at the following timepoints:  
 
During infusion: 15 min (± 3 min) and 30 min (± 3 min) 
 
Post-infusion: At EOI (±5 min), 1 hr (±5 min) and 2 hr (±10 min), 4 hrs (±10 min) following EOI.  On Cycle 1 Day 1 additional timepoints include 6 hrs (±10 min) and 8 hrs (±10 min) following 
EOI.  
 
Additional vital signs will be collected at the discretion of the investigator. 
3  Full physical examination to be performed at Screening (including height), Day 1 Predose, and End of Treatment; all other physical examinations may be symptom directed. Weight to be collected 
on Day 1. 
4  ECGs to be performed after the patient has been supine for at least 10 minutes. Readings should be performed with the patient in the same physical position.  ECG recording should be taken in 
triplicate with 5-10 minutes between readings.   
5  PK timepoints are as follows: 
• 
Cycle 1 Day 1: ALRN-6924 samples: within 1 hour before SOI; at EOI (+5 min) and at 30 min (±5 min), 1-hour (±5 min), 2 (±10 min), and 4 (±10 min) hours after EOI.   
• 
Cycle 1 Day 2: ALRN-6924 sample: 24 hours (±2 hours) post EOI; palbociclib: 18 hours (±2 hours) post dose 
• 
Cycle 1 Day 8 and 15: ALRN-6924 samples: within 1 hour before SOI; at EOI (+5 min), Palbociclib samples: within 1 hour before SOI; at EOI (+5 min) of ALRN-6924 dosing.  
• 
Cycle 1 Day 22: palbociclib: any time on Day 22 
6  During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. ALRN-6924 will be infused over 1 hour (±15 min). At the end of 
the infusion, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated. On days when both drugs are administered (Days 1, 8, and 15), palbociclib 
should be administered at least 6 hours following the infusion of ALRN-6924. It is recommended that palbociclib be administered with food at approximately the same time each day. 
7 Patients to record time of palbociclib administration in diary.  In addition, the number of capsules dispensed and returned should be recorded for each patient. 
 

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APPENDIX J:  Combination ALRN-6924 plus Palbociclib - Study Activities Cycle 2 and Beyond 
 
 
Day 11 
±3 d 
Day 8 
±1 d 
Day 15 
±1 d 
End-of-Treatment 
30 ± 5 d after last dose or 
at study withdrawal 
Long-Term 
Follow Up11 
Procedure 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
Pre-dose 
Post-dose 
 
 
Serum or urine pregnancy 
 
 
 
 
 
 
X 
 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam3 
X 
 
 
 
 
 
X 
 
Biopsy (NGS testing)4 
X 
 
Laboratory assessments – chemistry5 
X 
 
 
 
X 
 
X 
 
Laboratory assessments – hematology5 
X 
 
X 
 
X 
 
X 
 
Laboratory assessments – coagulation5 
X 
 
 
 
X 
 
X 
 
Collection of blood for immunogenicity6 
Cycle 2, 3, 5 only 
 
 
 
 
 
X 
 
Blood Collection- cell-free DNA6 
Cycle 5 only 
 
 
 
 
 
X 
 
ECOG Performance status7 
X 
 
X 
 
X 
 
X 
 
P53 status  
If a biopsy is collected at any time on study, p53 testing should be performed  
 
Tumor Assessment/Imaging 
Performed at end of even-numbered cycles (Cycle 2, 4, 6, etc.) prior to start of the next treatment 
cycle. After 1 year on treatment may be assessed after every third cycle, at the discretion of the 
investigator 
X8 
 
ALRN-6924 dosing9 
X 
 
X 
 
X 
 
 
 
Palbociclib dosing9 
Administered orally on Days 1 to 21 of each 28-day cycle with food 
 
 
Patient diary10 
Record daily during palbociclib dosing 
 
 
Concomitant medications 
Within 28 days prior to C1D1 until 30 days after last infusion or start of subsequent therapy 
X 
 
AE assessment 
 
X 
 
Phone calls or other contact 
 
 
 
 
 
 
 
X 
 
1  “Day 29” = Day 1 of next cycle for patients continuing treatment. Day 1 pre-dose evaluations for Cycle 2 and subsequent cycles are to be done within 3 days prior to next cycle drug administration. 
2  Blood pressure, pulse, respiration rate, body temperature. For patients on > 1 year, this procedure is no longer a mandatory study procedure. 
 
On the days of drug administration (Days 1, 8, 15 of each cycle), vital signs will be recorded pre-dose (within 30 minutes prior to SOI) and at the following timepoints:  
 
During infusion: 15 min (± 3 min) and 30 min (± 3 min) 
 
Post-infusion: At EOI (±5 min) and as clinically indicated following EOI.  
 
Additional vital signs will be collected at the discretion of the investigator.  

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3  Weight to be collected at Day 1 (or up to 3 days prior to Day 1) of each cycle. 
4  Biopsies are not required per protocol however if a biopsy is taken during the study a sample should be submitted to the central laboratory for next generation sequencing   
5  For patients on > 1 year, the required labs are: full labs to be collected on Day 1, and hematology only at Day 15 
6  Within 1 hour before SOI 
7  For patients on > 1 year, this is no longer a mandatory study procedure 
8  Same method used as baseline. Perform only if no tumor assessment was performed within 6-8 weeks prior. 
9  During the first two cycles, ALRN-6924 should be administered in the morning to allow observation of delayed infusion reactions. ALRN-6924 will be infused over 1 hour (±15 min). At the end of 
the infusion, IV fluids (saline) or oral fluids (500mL – 1000 mL) should be administered unless clinically contraindicated. On days when both drugs are administered (Days 1, 8, and 15), palbociclib 
should be administered at least 6 hours following the infusion of ALRN-6924. It is recommended that palbociclib be administered with food at approximately the same time each day. 
10  Patients to record time of palbociclib administration in diary.  In addition, the number of capsules dispensed and returned should be recorded for each patient. 
11  Phone calls or other contact should be made approximately every 2 months following end of treatment visit to assess survival status and collect information on subsequent therapies. 

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APPENDIX K:  RECIST 1.1 – Assessment of Clinical Activity for Patients with Solid Tumors  
 
Although response is not the primary endpoint of this study, patients with measurable disease will be 
assessed at baseline and during the study by standard criteria.  Patients should be reevaluated after 
receiving 2 cycles of study therapy and then after every 2 cycles thereafter.  In the event objective 
response (PR or CR) is noted, changes in tumor measurements must be confirmed by repeat assessments 
that should be performed at least 4 weeks after the criteria for response are first met.  For stable disease 
(SD), follow-up measurements must meet the SD criteria at least 5 weeks after study entry. 
1. 
Definitions 
Response and progression will be evaluated in this study using the international criteria (version 1.1) 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [Eur J Cancer. 45 
(2009) 228-247].  Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in RECIST 1.1.  Note: Lesions are either measurable or non-measurable using the criteria 
provided below.  The term “evaluable” in reference to measurability will not be used because it does not 
provide additional meaning or accuracy. 
1.1 
Measurable Disease 
Measurable disease is defined by the presence of at least one measurable lesion. Measurable lesions are 
defined as those that can be accurately measured in at least one dimension [longest diameter (LD) in the 
plane of measurement to be recorded] with a minimum size of:  
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable) 
• 
20 mm by chest x-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness no greater than 5 mm). 
1.2 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) are considered non-measurable disease.  Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses/abdominal organomegaly 
identified by physical exam and not followed by CT or MRI. 
Bone lesions, cystic lesions and lesions previously treated with local therapy must be considered as 
follows: 

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Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions.  However, these techniques can be used to confirm the presence or disappearance of bone 
lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be 
evaluated by cross sectional imaging techniques (i.e., CT or MRI) can be considered as measurable 
lesions if the soft tissue component meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable lesions, if they 
meet the definition of measurability described above.  However, if non-cystic lesions are present in 
the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in the 
lesion.  
1.3 
Target Lesions 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, representative 
of all involved organs, should be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or clinically).  A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. The baseline sum diameters will be used as 
reference by which to characterize the objective tumor response. 
1.4 
Lymph Node Assessment 
For lymph nodes, measurements should be made of the short axis, which is defined as perpendicular to 
the LD of node assessed in the plane of measurement: 
• 
Target lesion if short axis ≥ 15 mm 
• 
Non-target lesion if short axis is ≥ 10 but < 15 mm 
• 
Normal if short axis < 10 mm 
For baseline, add the actual short axis measurement to the sum of LD of non-nodal lesions. 

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1.5 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline.  Measurements of these lesions are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal progression.”  In 
addition, it is possible to record multiple non-target lesions involving the same organ as a single item on 
the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
2. 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 
4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up.  Imaging-based evaluation is preferred to evaluation 
by clinical examination when both methods have been used to assess the antitumor effect of a treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial and  
≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
When lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may be reviewed at the end of the study. 
Chest x-ray. Chest CT is preferred over chest x-ray, particularly when progression is an important 
endpoint.  Lesions on chest x-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.   
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness > 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is acceptable in certain 
situations (e.g., for body scans). 
Ultrasound (US). US should not be used to measure tumor lesions. US examinations cannot be 
reproduced in their entirety for independent review at a later date because they are operator dependent.  If 
new lesions are identified by US, confirmation by CT or MRI is advised.  If there is concern about 
radiation exposure at CT, MRI may be used instead of CT. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor markers. Tumor markers alone cannot be used to assess objective tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  
Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types such as germ cell tumors, 
where known residual benign tumors can remain). 

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3. 
Response Criteria 
3.1 
Evaluation of Target Lesions 
Complete Response (CR): 
 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 
mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. The 
appearance of one or more new lesions is also considered progression.  
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
3.1.1 
Assessment of Target Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis measurement recorded 
(measured in the same anatomical plane as the baseline exam), even if the nodes regress to below 10 mm 
on study.  In order to qualify for CR, each node must achieve a short axis < 10 mm.  For PR, SD and PD, 
the actual short axis measurement of the nodes is to be included in the sum of target lesions. 
3.1.2 
Target Lesions that Become “too small to measure” 
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g., 2 mm).  If it is the opinion of the radiologist that 
the lesion has disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned.   
3.1.3 
Lesions that Split or Coalesce on Treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining diameter measurements of each individual lesion.  If the lesions 
have truly coalesced such that they are no longer separable, the vector of the longest diameter should be 
the maximal longest diameter for the ‘coalesced lesion.’ 
3.2 
Evaluation of Non-target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non pathological in size 
(< 10 mm short axis). 
 

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Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions (The appearance 
of one or more new lesions is also considered progression).  To achieve 
‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease 
such that, even in the presence of SD or PR in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation. 
3.3 
New Lesions 
The finding of a new lesion should be unequivocal (i.e., not attributed to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than tumor, such 
as a ‘new’ healing bone lesion).  A lesion identified on a follow-up study in an anatomical location that 
was not scanned at baseline is considered a new lesion and will indicate disease progression.  If a new 
lesion is equivocal, continued therapy and follow-up evaluation will clarify if it represents truly new 
disease.  If repeat scans confirm this is definitely a new lesion, then progression should be declared using 
the date of the initial scan. 
3.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient’s best overall response assignment will depend on findings of 
both target and non-target disease and will also take into consideration the appearance of new lesions.  
Furthermore, depending on the nature of the study, it may also require confirmatory measurement. 
Specifically, in non-randomized trials where response is the primary endpoint, confirmation of PR or CR 
is needed to deem either one the “best overall response.”   
It is assumed that at each protocol-specified time point, a response assessment occurs.  The following 
table provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 

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Time point response: Patients with target (± non-target) disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD 
or 
not 
all 
evaluated 
No 
PR 
SD 
Non-PD 
or 
not 
all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease 
PD=progressive disease, NE=inevaluable 
 
Complete or partial responses may be claimed only if the criteria for each are confirmed by a repeat 
assessment at least 4 weeks later.  In this circumstance, the best overall response can be interpreted as 
shown in the following table: 

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Best overall response when confirmation of CR and PR required 
Overall response 
First time point 
Overall response 
Subsequent time point 
 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; 
NE=inevaluable 
* If CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met.  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in the fact patient had PR, not CR, at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
4. 
Confirmatory Measurement/Duration of Response 
4.1 
Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed at least 4 weeks after the criteria for response are first met. In the 
case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval at 5 weeks. 
4.2 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started). 

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The duration of overall CR is measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
4.3 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, taking 
as reference the smallest measurements recorded since the treatment started. 
 

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APPENDIX L: International Working Group Revised Response Criteria for Malignant Lymphoma 
(IWG) (2014)
 
“Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-
Hodgkin Lymphoma - The Lugano Classification” 
 
Cheson, B.D., Fisher, R.I., Barrington, S.F., Cavalli, F., Schwartz, L.H., Zucca, E., Lister, T.A. 
(September 20, 2014). Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma - The Lugano Classification. Journal of Clinical Oncology: 
32(27), 3059-3067.  
 
The published criteria authored by Cheson et al. may be viewed and/or downloaded by accessing the 
following website: 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.54.8800  (Abstract)  
 
 
  
Full Text, page 3062 
 
Table  2. Revised Staging System for Primary Nodal Lymphomas Stage                 
Involvement                      Extranodal (E) Status 
Limited 
I 
One node or a group of adjacent      Single extranodal lesions nodes        
without nodal 
involvement 
II 
Two or more nodal groups on the    Stage I or II by nodal same 
side of the diaphragm             extent with limited 
contiguous extranodal 
involvement 
II bulky*            II as above with “bulky” disease     Not applicable 
Advanced 
III 
Nodes on both sides of the              Not applicable 
diaphragm; nodes above the 
diaphragm with spleen 
involvement 
IV 
Additional noncontiguous                 Not applicable 
extralymphatic involvement 
 
NOTE. Extent of disease is determined by positron emission tomography– computed 
tomography for avid lymphomas and computed tomography for nonavid histologies. 
Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue. 
*Whether stage II bulky disease is treated as limited or advanced disease may be 
determined by histology and a number of prognostic factors. 
 
 
 
 
 
 
 

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Full Text, page  3064 
 
 
Response and Site 
Table  3. Revised Criteria for Response Assessment 
PET-CT–Based Response                                                                CT-Based Response 
Complete 
Lymph nodes and 
extralymphatic sites 
Nonmeasured lesion 
Organ enlargement 
New lesions 
Bone marrow 
Complete metabolic response 
Score 1, 2, or 3*  with or without a residual mass on 5PS† 
It is recognized that in Waldeyer’s ring or extranodal sites 
with high physiologic uptake or with activation within 
spleen or marrow (eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake may be greater than 
normal mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if uptake at 
sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic 
uptake 
Not applicable 
Not applicable 
None 
No evidence of FDG-avid disease in marrow 
Complete radiologic response (all of the following) 
Target nodes/nodal masses must regress to < 1.5 cm in LDi 
No extralymphatic sites of disease 
Absent 
Regress to normal 
None 
Normal by morphology; if indeterminate, IHC negative 
Partial 
Lymph nodes and 
extralymphatic sites 
Nonmeasured lesions 
Organ enlargement 
New lesions 
Bone marrow 
Partial metabolic response 
Score 4 or 5† with reduced uptake compared with baseline 
and residual mass(es) of any size 
At interim, these findings suggest responding disease 
At end of treatment, these findings indicate residual disease 
Not applicable 
Not applicable 
None 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy 
or an interval scan 
Partial remission (all of the following) 
≥ 50% decrease in SPD of up to 6 target measurable nodes 
and extranodal sites 
When a lesion is too small to measure on CT, assign 5 mm x 5 
mm as the default value 
When no longer visible, 0 x 0 mm 
For a node > 5 mm x 5 mm, but smaller than normal, use 
actual measurement for calculation 
Absent/normal, regressed, but no increase 
Spleen must have regressed by > 50% in length beyond 
normal 
None 
Not applicable 
No response or stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Nonmeasured lesions 
Organ enlargement 
New lesions 
Bone marrow 
No metabolic response 
Score 4 or 5 with no significant change in FDG uptake from 
baseline at interim or end of treatment 
Not applicable 
Not applicable 
None 
No change from baseline 
Stable disease 
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met 
No increase consistent with progression 
No increase consistent with progression 
None 
Not applicable 
Progressive disease 
Individual target nodes/nodal 
masses 
Extranodal lesions 
 
 
 
 
 
 
 
 
 
 
Nonmeasured lesions 
Progressive metabolic disease 
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or 
New FDG-avid foci consistent with lymphoma at interim or 
end-of-treatment assessment 
 
 
 
 
 
 
 
 
 
None 
(continued on following page) 
Progressive disease requires at least 1 of the following 
PPD progression: 
An individual node/lesion must be abnormal with: 
LDi > 1.5 cm and 
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions < 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen must increase to 
> 16 cm). If no prior splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly 
New or clear progression of preexisting nonmeasured 
lesions 
 
 

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Full Text, page 3065 
 
 
Response and Site 
 
Table 3. Revised Criteria for Response Assessment
(continued) 
 
 
New FDG-avid foci consistent with lymphoma rather 
than 
another etiology (eg, infection, inflammation). If
uncertain regarding etiology of new lesions, 
biopsy or interval scan may be considered 
Bone marrow 
New or recurrent FDG-avid
foci 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any axis; if < 1.0 
cm in any axis, its presence must be unequivocal 
and must be attributable to lymphoma 
Assessable 
disease 
of 
any 
size 
unequivocally 
attributable to lymphoma 
 
 
 
 
 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest
transverse diameter of a lesion; 
MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi,
shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan.
However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate
response (to avoid undertreatment). Measured dominant
lesions: Up to six of the largest dominant nodes, nodal masses, and
extranodal lesions selected to be clearly measurable in two diameters. Nodes should 
preferably be from disparate regions of the
body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those
in solid organs
(eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any
disease not
selected as measured, dominant disease and truly assessable disease should be considered not measured. These
sites include any nodes, nodal masses, 
and extranodal sites not selected as dominant or measurable or that do not meet the
requirements for measurability but are still considered abnormal, as well
as truly assessable disease, which is any site of
suspected disease that would be diffi to follow quantitatively with measurement, including pleural
effusions, ascites, bone
lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confi and followed by imaging. In
Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum
with complete metabolic
response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow
activation as a result of chemotherapy or myeloid
growth factors). 
 
†PET 5PS: 1, no uptake above background; 2, uptake ::: mediastinum; 3, uptake > mediastinum but ::: liver; 4, uptake moderately > liver;
5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 

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APPENDIX M: Response Assessment in Neuro-Oncology (RANO) Criteria 
 
“Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-
Oncology Working Group” 
 
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, DeGroot J, Wick W, 
Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, 
Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade 
gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin Oncol. 2010;28(11):1963-72. 
 
The published criteria may be viewed and/or downloaded by accessing the following website: 
http://ascopubs.org/doi/full/10.1200/JCO.2009.26.3541 
 
Selection of target lesions: 
To evaluate changes in brain tumors using the RANO criteria, up to 5 enhancing lesions identified on 
baseline T1 (T1 relaxation time constant)-weighted images are measured and monitored for response over 
time. 
 
 
 
 
Enhancing 
Non-measurable 
(At least 1 diameter <10 mm) 
Non-target 
Non-enhancing 
(Seen on T2/FLAIR) 
Measurable 
(2 perpendicular diameters ≥10 mm) 
Non-target 
Non-target 
Target 
Up to 5: 
•
Largest 
•
Reproducible 
The others 
All tumor lesions 

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Summary of response criteria:  
Criterion 
Complete 
Response 
Partial 
Response 
Stable Disease 
Progressive 
Disease 
T1 enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but <25% ↑ 
≥ 25% ↑a 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑a 
New lesion 
None 
None 
None 
Presenta 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NAb 
Clinical status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓a 
Requirement for response 
All 
All 
All 
Any 
Abbreviation: FLAIR = ﬂuid-attenuated inversion recovery; NA=not applicable 
a Progression occurs when this criterion is present. 
b Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration. 
 

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APPENDIX N: iRECIST Response Criteria 
 
“iRECIST: Guidelines for Response Criteria for Use in Trials Testing Immunotherapeutics” 
 
Seymour, L., Bogaerts, J., Perrone, A., Ford, R., Schwartz, L.H., Mandrekar, S., et al. (2017). iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol, 18(3), e143-
e152. DOI: https://doi.org/10.1016/S1470-2045(17)30074-8 
 
The published criteria may be viewed and/or downloaded by accessing the following website: 
http://recist.eortc.org/wp-content/uploads/2017/03/Supplementary-material_iRECIST_Seymour-et-
al_revision_FINAL_clean_nov25.pdf 

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APPENDIX O:  NCI Common Terminology Criteria for Adverse Events, Version 4.03 
 
Version 4.03 of the NCI CTCAE, dated 14 June 2010, may be viewed and/or downloaded by accessing 
the following website:   
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf