Conditions: Granulosa Cell Ovarian Cancer Low Grade Serous Ovarian/ Primary Peritoneal Cancer Endometrioid Endometrial Cancer
Keywords: Onapristone ER (Apristor) Oral Progesterone Progesterone Receptor Positive (PR+) Anastrozole 19-061
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
The purpose of this study is to test any good and bad effect of the study drug, onapristone extended-release (ER) alone and in combination with anastrozole.

Detailed description:

Arms:
arm 1: Enrolled patients will initiate treatment with onapristone ER 50 mg by mouth twice daily, about 12 hours apart, beginning Day 1 of Cycle 1. A Cycle is 28 days. This Arm is CLOSED. arm 2: Enrolled patients will initiate treatment with onapristone ER 50 mg by mouth twice daily, about 12 hours apart, beginning Day 1 of Cycle 1. A Cycle is 28 days arm 3: Enrolled patients will initiate treatment with onapristone ER 50 mg by mouth twice daily, about 12 hours apart, beginning Day 1 of Cycle 1. A Cycle is 28 days arm 4: Enrolled patients will initiate treatment with onapristone ER 50 mg by mouth twice daily, about 12 hours apart and anastrozole 1mg po QD in AM beginning Day 1 of Cycle 1. A Cycle is 28 days.

Interventions: intervention 1: Onapristone ER intervention 2: Onapristone ER + Anastrozole
Intervention descriptions: intervention 1: 50 mg PO BID (with dosage adjustments) until POD, unacceptable toxicity or withdrawal of consent. intervention 2: Onapristone ER Patients will take 50 PO BID in the form of two 20 mg tablets and one 10 mg tablet taken with food and water twice daily. Patients will be prescribed anastrozole 1mg PO QD. Anastrozole will be taken once daily in the AM with patients morning dose of onapristone ER.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
 
MSK PROTOCOL COVER SHEET 
 
Basket Study of the Oral Progesterone Antagonist Onapristone ER (Apristor), Alone 
or In Combination With Anastrozole in Women with Progesterone Receptor Positive 
(PR+) Recurrent Granulosa Cell Tumor, Low Grade Serous Ovarian Cancer or 
Endometrioid Endometrial Cancer 
 
 
Principal Investigator/Department: 
Rachel Grisham, MD / Medicine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 4 
3.0 
BACKGROUND AND RATIONALE ........................................................................................ 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION................................................................. 7 
4.1 
Design ................................................................................................................................. 7 
4.2 
Intervention .......................................................................................................................... 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................ 8 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 10 
6.1 
Subject Inclusion Criteria ................................................................................................... 10 
6.2 
Subject Exclusion Criteria .................................................................................................. 11 
7.0 
RECRUITMENT PLAN ......................................................................................................... 12 
8.0 
PRETREATMENT EVALUATION ......................................................................................... 12 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 13 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ...................................................... 15 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................ 17 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 20 
13.0 CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 26 
14.0 BIOSTATISTICS ................................................................................................................... 26 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES .... 28 
15.1 Research Participant Registration ...................................................................................... 28 
15.2 Randomization................................................................................................................... 28 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 30 
16.1 Quality Assurance ............................................................................................................. 30 
16.2 Data and Safety Monitoring ............................................................................................... 30 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................................... 31 
17.1 Privacy .............................................................................................................................. 31 
17.2 Serious Adverse Event (SAE) Reporting ............................................................................ 31 
18.0 INFORMED CONSENT PROCEDURES ............................................................................... 32 
19.0 REFERENCES ..................................................................................................................... 34 
20.0 APPENDICES ....................................................................................................................... 34 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is an investigator initiated, open label, single institution basket study of the oral 
progesterone antagonist, onapristone ER (Apristor), alone or in combination with 
anastrozole, in women with selected progesterone receptor positive (PR+) recurrent 
gynecologic cancers. This study will enroll women with recurrent or advanced granulosa cell 
tumor, low grade serous ovarian cancer, or endometrioid endometrial cancer who have 
measurable disease and have progressed following at least one prior line of chemotherapy. 
Eligible patients will be progesterone receptor positive by immunohistochemistry (IHC), 
defined as ≥ 1% positivity displayed on archival tissue. Biopsy will be performed if no archival 
tissue is available or if archival tissue was taken more than 3 years prior . 
Cohorts will be defined by histology with Cohort 1 enrolling patients with granulosa cell tumor 
to treatment with single agent onapristone ER 50 mg PO BID, Cohort 2 enrolling patients 
with low grade serous ovarian cancer to treatment with single agent onapristone ER, and 
Cohort 3 enrolling patients with endometrioid endometrial cancer to treatment with single 
agent onapristone ER. Cohorts 2 and 3 were closed to accrual in March of 2021 due to poor 
accrual as new treatments have become available for these diseases during the course of 
this study (endometrioid accrued 1 patient, low grade serous ovarian cancer accrued 5 
patients). Cohort 1 completed accrual to stage 1 and has shown stable disease in 9 out of 14 
patients patients with recurrent PR+ granulosa cell cancer treated with single agent 
onapristone ER at 50mg PO BID with ongoing responses lasting > 9 months in 2 patients. 
However, no RECIST 1.1 Criteria complete or partial responses have been seen. Cohort 4 
will enroll patients with PR+ granuloasa cell tumor to onapristone ER 50mg PO BID in 
combination with anastrozole 1mg PO daily. 
 
Treatment 
Histology 
Stage I 
Stage II 
Response 
(expansion) 
rate to be 
deemed 
worthy of 
further 
study 
Cohort 
Onapristone PR+ 
Enroll 14 
Expand to a 
≥ 3/23 
1 
ER 
Granulosa cell 
patients, if ≥ 1 
total of 23 
tumor 
response(s) 
patients 
expand to 
Stage II 
Cohort 
Onapristone PR+ Low 
Enroll 16 
Expand to a 
≥ 5/25 
2 
ER 
grade serous 
patients, if ≥ 2 
total of 25 
ovarian cancer 
responses 
patients 
expand to 
Stage II 
Cohort 
Onapristone PR+ 
Enroll 19 
Expand to a 
≥ 11/36 
3 
ER 
Endometrioid 
patients, if ≥4 
total of 36 
endometrial 
responses 
patients 
cancer 
expand to 
Stage II 
Cohort 
Onapristone PR+ 
Enroll 14 
Expand to a 
≥ 3/23 
4 
ER + 
Granulosa cell 
patients, if ≥ 1 
total of 23 
Anastrozole 
tumor 
response(s) 
patients 
expand to 
Stage II 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
 
All enrolled patients will be treated at the recommended phase II dose (RP2D) of onapristone 
ER alone (cohort 1-3) or in combination with anastrozole (cohort 4) and continue on 
treatment until progression of disease, intolerable toxicity, or patient refusal. This study is 
expected to enroll between 34 and 43 patients, enrolling 1-2 patients per month. The study is 
expected to complete accrual within 12-24 months. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
The following objectives will apply to each of the three Cohorts (patient populations) 
Primary Objective: 
1) To evaluate the efficacy, in terms of response rate (CR or PR) of onapristone ER as a single 
agent or in combination with anastrozole, as determined by RECIST 1.1 response within 36 
weeks of treatment, in patients with PR+ recurrent or advanced granulosa cell tumor, low 
grade serous ovarian cancer, or endometrioid endometrial cancer. 
 
Secondary Objectives: 
1) To evaluate the safety and tolerability of onapristone ER alone or in combination with 
anastrozole in this patient population. 
 
2) To evaluate the duration of response, clinical benefit rate (CR, PR, SD lasting for ≥16 weeks) 
and progression free survival (PFS) of patients with PR+ recurrent or advanced low grade 
serous ovarian cancer, granulosa cell tumor or endometrioid endometrial cancer treated with 
onapristone ER alone or in combination with anastrozole. 
 
Exploratory: 
3) To correlate the level of PR positivity (as a continuous variable) with response to therapy 
(defined as complete or partial response) with onapristone ER alone or in combination with 
anastrozole. 
 
4) To correlate the level of phosphorylated PR (as a continuous variable) with response to 
therapy with onapristone ER alone or in combination with anastrozole. 
 
5) To correlate the level of PR target gene expression (as a continuous variable) with response 
to therapy (defined as complete or partial response) with onapristone ER alone or in 
combination with anastrozole. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Onapristone Background 
Apristor, extended release onapristone, is a type I full progesterone antagonist that inhibits 
progesterone hormone-mediated PR activation and stabilizes PR association with corepressors. 
Onapristone has shown activity across multiple preclinical models of hormonally driven cancer. The 
development of immediate release onapristone was previously halted by Schering AG after liver 
function test abnormalities were observed; however, after further review the majority of these LFT 
elevations were found to be due to alternative causes and have not been seen as a significant issue 
with the reformulation of onapristone to an extended release version (Apristor). The clinical utility of 
Apristor is now being reevaluated and developed through Context Therapeutics. 
Under the Context Therapeutics development program to date, 12 healthy female volunteers have 
received a single dose of 10 mg immediate release (IR) onapristone, 31 male patients with prostate 
cancer and 52 females with PR-positive breast, ovarian, and endometrial tumors have received 
doses of 10-50 mg onapristone ER BID or 100 mg/day of onapristone IR [[1-4]]. 
There were no grade 4 treatment-related AEs reported to date. The majority of adverse events were 
grade 1 or 2. Grade 3 adverse events were reported in 12 patients (16%) patients: GGT increase 
(5%), AP and AST increases (3% each), and nausea and anorexia (1% each). 
The most common related AEs reported (all grades) were asthenia (16%), GGT increase (15%), 
nausea (14%), AST increase (12%), and ALT increase (11%). Two patients discontinued 
onapristone due to AEs. One patient discontinued due to three unrelated AEs (anemia, 
thrombocytopenia and leucopenia) in the context of bone marrow failure due to progressive bone 
metastases. The other patient had a 25% dose reduction for hepatic toxicity and subsequently 
discontinued onapristone due to disease progression/LFT abnormalities. 
One death has been reported within 30 days of discontinuing onapristone; respiratory distress due to 
progression of lung metastases. 
The PK and food effect study results from a phase I study in healthy subjects observed a half-life 
(t1/2) of 4.2h for an oral immediate-release (IR) formulation of onapristone administrated in fasting 
conditions. The same study observed a minor food effect on the maximum plasma concentration 
(Cmax) of onapristone and its metabolite M1 with an approximate average decrease of 18% and an 
average increase in AUC∞ of approximately 13%. 
 
 
 
 
3.2 Prior Clinical Data with Onapristone from Breast Cancer Studies : 
A non-randomized, open, multicenter phase 2 study was conducted between December 1991 and 
May 1995 at 13 sites in Germany and the United Kingdom[5]. The study goal was to investigate the 
efficacy and safety of onapristone when given 100 mg/day to post-menopausal women with 
advanced breast cancer that had progressed on tamoxifen. Of the 101 evaluable patients, one had a 
complete response (CR), 9 had a partial response (PR), and 39 had SD for three months or more. 
This resulted in an overall clinical benefit of 49%. The median duration of the CR + PR was 11 
months and the median duration for patients with SD was seven months. The responses seen in the 
group of 33 evaluable patients with PR-positive primary tumors were promisimg with 4 (12%)patients 
displaying a partial response, 15 (45%) patients with stable disease. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
A phase 2 study investigating onapristone as first-line endocrine therapy in patients with breast 
cancer was conducted as an investigator initiated study [6]. The study enrolled 19 patients before 
Schering AG closed the study in 1995 when the decision was made to halt the development of the 
immediate release formulation of onapristone. 
 
Of the 19 patients entered into the study prior to study closure, one discontinued therapy after 
4.5 months because of a marked elevation in the patient’s LFT’s. At that time, the patient had SD. 
The elevated LFTs rapidly returned to normal after discontinuation of onapristone. Of the remaining 
18 patients, 10 (56%) showed a PR and two (11%) durable SD (≥6 months), giving an overall tumor 
benefit rate of 67%. The median duration of objective response and SD was 16.2 months. The 
majority of patients had hormone-receptor-positive tumors. Ten patients were 
ER-positive/PR-positive, of whom seven achieved PR, 1 had SD. Six patients had 
ER-positive/PR-negative tumors, of whom two achieved PR and two had SD. No response was seen 
in the remaining two patients who had ER-negative/PR-negative tumors. 
 
3.3 Anastrozole for Recurrent Granulosa Cell Cancer: 
 
Anastrozole is a potent and selective nonsteroidal aromatase inhibitor. By inhibiting aromatase, the 
conversion of androstenedione to estrone, and testosterone to estradiol, is prevented, thereby 
decreasing tumor mass or delaying progression in patients with tumors responsive to hormones. 
Anastrozole causes an 85% decrease in estrone sulfate levels. 
Aromatase inhibitors are commonly used to treated recurrent granulosa cell tumors based on low 
response rates to chemotherapy and historically high rates of ER/PR expression within these 
tumors.However, objective response rate remains low, and was found to be 2.5% in the prospective 
phase II PARAGON study on anastrozole 1mg po QD in patients with recurrent granulosa cell 
tumors (Banerjee, JCO, 2018). 
 
 
3.4 Rationale for Current Study: 
A phase I dose escalation study of onapristone ER in progesterone receptor positive (PR+) breast, 
endometrial, and ovarian cancer patients found all doses tested to be safe and well tolerated, with 
50mg PO BID recommended as the phase 2 dose. The most common treatment-related adverse 
events reported were nausea, fatigue and constipation. In that phase I study patients with heavily 
pretreated granulosa cell ovarian cancer, low grade serous ovarian cancer, and endometrial cancer 
were seen to have tumor stabilization for at least 16 weeks [3]. These are hormonally driven 
gynecologic cancers which generally have poor responses to chemotherapy and limited treatment 
options. This phase II study currently ongoing at Memorial Sloan Kettering Cancer Center has 
enrolled 14 patients with recurrent PR+ granulosa cell cancer and exhibited SD in 9 out of 14 
patients treated, with minimal adverse events reported. We now seek to test the combination of 
Onapristone ER in combination with anastrozole to hopefully enhance the response rate in patients 
with PR+ granulosa cell cancer. 
While prospective data is lacking in patients with low grade serous ovarian cancer the retrospective 
response rate to chemotherapy is 4%, and 9% to available hormonal therapies [7, 8]. Granulosa cell, 
the most common type of sex-cord stromal ovarian cancer, generally has poor response rates to 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
chemotherapy and is commonly treated with hormonal strategies in the recurrent setting based on 
retrospective data. The first prospective study of anastrozole in patients with recurrent ER/PR + 
granulosa cell tumors was recently reported and demonstrated a 2.5% response rate, clearly 
demonstrating a need for further treatment options for this disease[9]. Endometrial cancer also has 
limited options with a 13% response rate to chemotherapy in the second line [10]. Megestrol acetate 
is the only systemic treatment FDA approved specifically for endometrial cancer and has shown 
response rates as high as 24% in conjunction with tamoxifen in the recurrent setting, but is not 
commonly used due to poor tolerance [11]. 
Apristor (onapristone ER) is a well-tolerated oral full progesterone antagonist which has shown 
promising preliminary findings in gynecologic cancer based on a dose escalation study [[3]]. 
Granulosa cell ovarian cancer, low grade serous ovarian cancer and endometrioid endometrial 
cancer are hormonally driven gynecologic cancers with poor response rates to chemotherapy and 
limited treatment options available. We hypothesize that oral onapristone ER 50 mg PO BID will be 
active across multiple histologic types of PR+ gynecologic cancer. To test this hypothesize we will 
implement a basket study of onapristone ER in PR+ granulosa cell ovarian cancer, low grade serous 
ovarian cancer and endometrioid endometrial cancer with recurrent or advanced measurable 
disease, which has progressed following at least one line of chemotherapy and in combination with 
anastrozole 1mg po QD will be active in patients with PR+ granulosa cell tumors.. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is an open-label, single institution, investigator-initiated study of extended release 
onapristone alone or in combination with anastrozole in patients with PR+ granulosa cell, low 
grade serous ovarian cancer, or endometrioid endometrial cancer who have measurable 
disease and have progressed following at least 1 prior line of chemotherapy. These 
histologies have been chosen for further exploration based on the results of an earlier phase 
I study of extended release onapristone showing preliminary efficacy in these histologies, the 
hormonally responsive nature of these histologies, and the limited available options for 
systemic therapy of granulosa cell tumors, low grade serous ovarian cancer, and 
endometrioid endometrial cancer, with historically low response rates to systemic therapy. 
This study will determine the efficacy of extended release onapristone and determine those 
gynecologic histologies worthy of further development. 
4.2 
Intervention 
Patients with the histologies of interest (granulosa cell tumor, low grade serous ovarian 
cancer, or endometrioid endometrial cancer) with recurrent disease will be screened for 
eligibility. Patients must have archival tissue available which is positive for expression of the 
progesterone receptor (≥ 1% PR+ by IHC). If archival tissue has not previously been 
screened for presence of the progesterone receptor as part of routine diagnostic review, then 
archival tissue must be available for IHC analysis. Patients who do not have archival tissue 
available, or have archival tissue that was taken more than 3 years prior, will undergo a 
biopsy in line with what is medically appropriate for their disease. Patients will not be put at 
undue risk to obtain fresh tissue biopsy to determine study eligibility as procedures more 
invasive than a core biopsy should not be utilized; in other words, a procedure to obtain 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
biopsy should have a serious/severe complication risk no greater than 2%. The ICH analysis 
on baseline samples will be non-billable. 
All enrolled patients will be treated with onapristone ER at the recommended phase 2 dose 
of 50mg PO BID or in combination with anastrozole 1mg po QD (cohort 4). Study drugs will 
be self-administered by patients. Patients will take onapristone ER and anastrozole with food 
and water. A cycle is 28 days. Patients will be required to maintain a pill diary to record each 
dose of drug taken. All toxicities will be graded using CTCAE version 5.0. Toxicities will be 
evaluated during physician assessments performed every 2 weeks during the first cycle and 
every 4 weeks during subsequent cycles of treatment with onapristone ER with or without 
anastrozole. 
Patients will continue to receive study treatment until disease progression (as defined by 
RECIST 1.1), unacceptable toxicity or withdrawal of consent. 
 
All cohorts (granulosa cell tumor, low grade serous ovarian cancer, endometrioid 
endometrial cancer) will enroll in parallel, with expansion from stage I to stage II when 
the prespecified response criteria are met for each cohort as described in the table 
below. 
 
Treatment 
Histology 
Stage I 
Stage II 
Response 
(expansion) 
rate to be 
deemed 
worthy of 
further study 
Cohort 1 
Onapristone ER 
PR+ Granulosa 
Enroll 14 
Expand to a total of 
≥ 3/23 
cell tumor 
patients, if ≥ 1 
23 patients 
response(s) 
expand to Stage 
II 
Cohort 2 
Onapristone ER 
PR+ Low grade 
Enroll 16 
Expand to a total of 
≥ 5/25 
serous ovarian 
patients, if ≥ 2 
25 patients 
cancer 
responses 
expand to Stage 
II 
Cohort 3 
Onapristone ER 
PR+ 
Enroll 19 
Expand to a total of 
≥ 11/36 
Endometrioid 
patients, if ≥4 
36 patients 
endometrial 
responses 
cancer 
expand to Stage 
II 
Cohort 4 
Onapristone ER 
PR+ Granulosa 
Enroll 14 
Expand to a total of 
≥ 3/23 
+ Anastrozole 
cell tumor 
patients, if ≥ 1 
23 patients 
response(s) 
expand to Stage 
II 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Pharmacokinetics 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
In a Phase 1 dose escalation trial, Apristor AUC and Cmax were dose-proportional across 
dose levels. Average Tmax was 3.01 hours (2.71-3.2) vs 1.84 hours for 10-50 mg with a 60% 
(+/- 20) relative bioavailability. Steady state was attained before day 8 and the mean 
minimum concentrations at steady state were up to 5 times those obtained at day 1. There 
was no evidence of accumulation at day 57. The observed mean t1/2 was approximately 
18.01 hours (range, 13.9 to 37), consistent with steady state achievement before day 8. 
Plasma concentration versus time curves suggest biphasic elimination [[3]]. 
 
5.2 Onapristone Extended Release Tablets 
 
Onapristone is a yellow to green solid with a melting point of 155°C. Onapristone is a weak 
base with a pKa of 5.15 (± 0.15). The logP is 4.03 and the logD is 3.97. Onapristone is 
slightly to very slightly soluble in aqueous buffer solutions at acidic pH up to pH 5.0 (pH 1.2, 
2.0, 3.0 and 5.0). There is a decrease in solubility at pH values 6.0 – 8.0. Multiple drug 
product formulations of onapristone have been developed for evaluation throughout the 
clinical development program. The focus of further development and in this study will be 
Onapristone ER Tablets. 
Onapristone extended release tablets are available in 10mg and 20mg form. Patients will 
take 50 PO BID in the form of two 20 mg tablets and one 10 mg tablet taken with food and 
water twice daily. Uncoated round tablets are being phased out as inventory diminishes. 
Patients enrolled to this study will be treated with either coated or uncoated tablets, 
depending on available inventory. The coated tablets used in this study will be pink and 
yellow film coated oval tablets (10 and 20mg, resp.). Coated and uncoated tablet core 
formulations are the same to release the drug at similar rates. The coating is water soluble. 
 
 
Quantitative Composition of Onapristone Extended-Release Tablets 
 
Component 
Quality 
Standard 
Function 
Amount (mg) 
2.5 
mg 
5 mg 
10 
mg 
20 mg 
Onapristone1 
In-house 
API 
2.50 
5.00 
10.00 
20.00 
Microcrystalline 
cellulose 
USP and 
Ph.Eur. 
filler 
20.5 
20.5 
20.5 
20.5 
Lactose 
monohydrate 
USP and 
Ph.Eur. 
filler 
10.25 
20.50 
41.00 
82.00 
Pregelatinized 
Starch 
USP and 
Ph.Eur. 
disintegrant 
10.00 
20.00 
40.00 
80.00 
Hydroxypropyl 
Methylcellulose 
USP/NF and 
Ph.Eur. 
Binder/ 
modified 
release agent 
16.50 
33.00 
66.00 
132.00 
Colloidal silicone 
dioxide 
USP/NF and 
Ph.Eur. 
glidant 
0.25 
0.50 
1.00 
2.00 
Magnesium 
stearate 
USP/NF and 
Ph.Eur. 
lubricant 
0.25 
0.50 
1.00 
2.00 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
Total tablet 
weight (mg) 
- 
- 
50 
100 
200 
400 
1The weight of drug substance is adjusted per the assay value of onapristone on an “as-is” 
basis. As required, the difference in weight is adjusted with hydroxypropyl methylcellulose. 
5.3 Onapristone Storage and Labeling 
 
The tablets are stored under ambient conditions, at 15-30 °C. 
Select batches of onapristone ER tablets are on ICH stability programs at 25 ± 2 °C/60 ± 5% 
(long-term condition) and 40 ± 2 °C/75 ± 5% (accelerated condition). An intermediate 
condition of 30 ± 2 °C/65 ± 5% RH is being utilized as backup condition. For batches with 
the longest-term stability data, no significant changes in the appearance, potency (assay), 
impurity profile or dissolution profile have been observed after 6 months at the accelerated 
storage condition (40 °C/75% RH) and 18 months at the long-term storage condition (25 
°C/60% RH). Based on ICH Q1A(R2) and Q1E guidance, the shelf life for ER tablets is 
currently set at 30 months. 
5.4 Anastrozole 
Anastrozole is an aromatase inhibitor which is commercially available and a standard of care 
treatment for recurrent granulosa cell cancer. It should be stored at room temperature. 
Commercial supply will be used. Patients will be prescribed anastrozole 1mg PO QD. 
Anastrozole will be taken once daily in the AM with patients morning dose of onapristone ER. 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
• 
Histologically confirmed diagnosis at MSK of either (1) granulosa cell ovarian cancer, (2) 
low grade serous ovarian/ primary peritoneal cancer, or (3) endometrioid endometrial 
cancer; with PR expression ≥1% by IHC on archival tissue taken within the prior 3 years 
or new biopsy if no archival tissue is available. IHC results do not have to be from MSK. 
• 
Measurable disease as defined by RECIST 1.1. Measurable disease is defined as at 
least one lesion that can be accurately measured in at least one dimension. Each lesion 
must be ≥10mm when measured by CT or MRI. Lymph nodes must be ≥15mm in short 
axis when measured by CT or MRI 
• 
Patients must have had one prior chemotherapy regimen for management of disease. 
Note: additional lines of chemotherapy, biologic or immunotherapy are allowed. 
• 
Recovery from effects of recent surgery, radiotherapy, or chemotherapy 
o At least 4 weeks out from their last dose of radiation therapy 
o At least 4 weeks post-op from any major surgical procedure 
o At least 3 weeks out from their last dose of chemotherapy and/or biologic/targeted 
therapy 
• 
Must be ≥ 18 years of age 
• 
Karnofsky Performance Status (KPS) of ≥ 70% 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
• 
Women of child-bearing potential must have a negative pregnancy test within 14 days 
prior to commencement of study treatment 
• 
Women of child bearing potential must use an effective form of contraception during 
study and for at least 6 months after completion of study treatment 
• 
Laboratory Test Findings performed within 14 days prior to initiation of study drug 
showing: 
▪ 
Bone marrow function: 
• 
Absolute neutrophil count (ANC) ≥ 1,000/mcL 
• 
Platelets ≥ 75,000/mcL 
• 
Hemoglobin ≥ 8 g/dL 
▪ 
Renal function: 
• 
Creatinine ≤ 1.5 x ULN 
▪ 
Hepatic function: 
• 
Bilirubin ≤ 1.5 x ULN 
• 
AST and ALT ≤ 2.5 x ULN 
• 
Resolution of all acute toxic effects of prior therapy to NCI CTCAE (Version 5.0) Grade ≤ 
1, with the exception of unresolved Grade 2 neuropathy and Grade 2 alopecia, which are 
allowed 
• 
Patient has recovered from any prior radiotherapy 
• 
Patients must be able to swallow tablets whole, without crushing 
 
 
 
 
6.2 
Subject Exclusion Criteria 
• 
History of another invasive malignancy (other than non-melanoma skin cancer or 
curatively treated in situ carcinoma) with evidence of disease within the past 3 years 
• 
History of prior hormonal therapy (i.e., megesterol acetate, tamoxifen or aromatase 
inhibitors) for treatment of cancer within 28 days before starting study drug 
• 
Any psychological, familial, sociological or geographic condition that would potentially 
hamper compliance with the study protocol 
• 
Known brain metastasis which have not been treated or showed stability for ≥ 6 months 
• 
Patient has received an oral or IV corticosteroid within the prior 28 days and requires 
chronic corticosteroid therapy (excludes use of steroid premeds for CT allergy) 
• 
Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95mmHg) 
despite medical treatment. Patients with a history of hypertension are allowed 
provided blood pressure is controlled by anti-hypertensive treatment. 
• 
Clinically significant heart disease as evidenced by myocardial infarction or arterial 
thrombotic event within the past 6 months, severe or unstable angina, or New York 
Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction 
measurement of < 50% at baseline 
• 
Refractory nausea and vomiting, requirement for parenteral hydration and/or 
nutrition, drainage gastrostomy tube, malabsorption, external biliary shunt, or 
significant small bowel resection that would preclude adequate study drug 
absorption 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
• 
Anticipated or ongoing administration of anti-cancer therapies other than those 
administered in this study 
• 
Use of any prescription medication during the prior 28 days of first onapristone 
dosing that the investigator judges is likely to interfere with onapristone activity; 
specifically strong inhibitors or inducers, or sensitive substrates of cytochrome 
P450 CYP3A4. Investigators should consult the following table of clinically- 
relevant products http://medicine.iupui.edu/CLINPHARM/ddis/clinical-table. 
 
7.0 
RECRUITMENT PLAN 
Patients will be recruited from the patients seen by the Gynecologic Medical 
Oncology (GMO) Service, Department of Medicine, at Memorial Sloan Kettering 
Cancer Center (MSKCC). The investigator will screen patients with granulosa cell 
ovarian cancer, low grade serous ovarian cancer, and endometrioid endometrial 
cancer to see if they are eligible for this trial. 
During the initial conversation between the investigator/research staff and the patient, 
the patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review 
portions of their medical records at MSKCC in order to further assess eligibility. They 
will use the information provided by the patient and/or medical record to confirm that 
the patient is eligible and to contact the patient regarding study enrollment. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
Screening: 
• 
Signature of screening informed consent if PR testing has not yet been 
performed (signature of prescreening consent is not needed if PR status is already 
available from archival tissue) 
• 
Tumor biopsy or paracentesis, if no archival tissue is available within past 
3 years 
• 
Verification of ≥1% PR+ by IHC in tumor tissue, if not previously performed 
To be completed within 30 days prior to start of study 
drug: 
• 
Signature of treatment informed consent following inclusion and exclusion 
review and determination of patient eligibility for the study 
• 
Physical exam and vital signs (height, weight, pulse, temperature, blood 
pressure) 
• 
Karnofsky Performance Status (KPS) 
• 
12-lead electrocardiogram (ECG) 
• 
Baseline radiographic tumor assessment (CT or MRI of abdomen and pelvis; 
CT of chest) with documentation of sites of disease per RECIST (version 1.1) 
• 
Bone density (if not performed within 12 months prior to start of therapy) 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
To be completed within 14 days prior to start of study drug: 
• 
Pregnancy test in women of child bearing potential 
• 
Blood sampling for: 
o CBC with differential 
o Comprehensive Metabolic Panel (Na, K, Cl, CO2, BUN, CREAT, Ca, 
Glucose, Bilirubin, total protein, albumin, alkaline phosphatase, AST, 
ALT) 
o Coagulation tests (PT, PTT, INR) 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 Treatment Plan 
Enrolled patients will initiate treatment with onapristone ER 50 mg by mouth twice 
daily, about 12 hours apart, and anastrozole 1mg po QD in AM (if in cohort 4) 
beginning Day 1 of Cycle 1. A Cycle is 28 days. Onapristine ER tablets should be 
swallowed whole with a glass of water and food l. Onapristone ER and anastrozole 
should be taken at the same times each day. Missed doses will not be made-up. 
Vomited doses should not be retaken. All doses and missed doses will be recorded in 
the patient’s pill diary. Patients will remain on treatment with onapristone ER 50 mg PO 
BID alone (cohorts 1-3) or with anastrozole 1 mg po QD (cohort 4) (with dosage 
adjustments as described below) until POD, unacceptable toxicity or withdrawal of 
consent. 
While on study, patients will return for assessments with a treating physician every 2 
weeks during the first cycle, and then every 4 weeks. Vital signs, toxicity assessment 
and blood work will be performed at each start of cycle visit. The pill diary will be 
collected, and a new drug supply and pill diary will be provided. A +/- 4 day window is 
allowed for each start of cycle assessment. 
Within 30 days of starting treatment, every 8 weeks from Cycle 1 Day 1 while on 
treatment, and at end of study, patients will have a CT of chest, abdomen and pelvis 
performed, or MRI of abdomen and pelvis with CT of chest. Best overall response 
should be confirmed with repeat imaging performed at ≥ 4 weeks. There is a +/- 7 day 
window for completion of interval tumor assessments by imaging. 
An optional research non-billable tumor biopsy will be performed at end of treatment in 
consenting patients with accessible disease. 
 
9.2 Overview of Dose Adjustments for Onapristone ER Toxicity 
 
Any dose modification of onapristone ER requires consultation with the study PI. 
• 
If Grade 1 or 2 toxicities occur, give supportive care per institutional guidelines. 
No onapristone ER dose reduction should occur unless discussed with study PI. 
 
• 
If ≥ Grade 3 toxicities occur that are considered potentially related to onapristone 
ER, including headache, nausea, vomiting, LFT elevation or diarrhea, hold 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
onapristone ER until the toxicity resolves to ≤ Grade 1 (unless was Grade 2 at 
baseline, then when returns to baseline). If onapristone ER is held for LFT 
elevation, then LFT levels should be checked weekly until ≤ Grade 1 or baseline, 
and then onapristone ER resumed with dose reduction as per table below. 
 
• 
If onapristone ER is held for ≤28 days it may be restarted at the same or a reduced 
dose at the discretion of the treating physician (except in the case of LFT elevation, 
which requires dose reduction). 
 
• 
If onapristone ER is held for >28 days the drug should be permanently discontinued. 
Patients may continue on anastrozole as a single agent if onapristone ER is held 
Onapristone dose reductions will occur as per the table below: 
 
Starting Dose 
50 mg PO BID 
Dose Reduction #1 
30 mg PO BID 
Dose Reduction #2 
10 mg PO BID 
Dose Reduction #3 
Permanently Discontinue 
 
9.3 Dose Adjustment for Anastrozole Toxicity 
No dose adjustments of anastrozole will occur. 
• 
If Grade 1 or 2 toxicities occur, give supportive care per institutional guidelines. 
 
• 
If ≥ Grade 3 toxicities occur that are considered potentially related to anastrozole 
(with the exception of osteoporosis or alopecia) hold anastrozole until the toxicity 
resolves to ≤ Grade 1 (unless was Grade 2 at baseline, then when returns to 
baseline). 
 
• 
If anastrozole is held for ≤28 days, it may be restarted at the same dose at the 
discretion of the treating physician 
 
• 
If anastrozole is held for >28 days, the drug should be permanently discontinued 
Patients may continue on onapristone ER as a single agent if anastrozole is held 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Screening 
Pre- 
Treatment9 
Day 13; 
Cycle 1 
Day 15; 
Cycle 13 
Day 1; 
Cycle 3, 5, 
7… (odd 
cycles)3 
Day 1; 
Cycle 2, 4, 
6… (even 
cycles)3 
End of 
Study 
Treatment 
Follow up5 
Safety 30 
day & 
Survival 
Follow up 
Informed 
Consent 
X 
X 
History & 
Physical 
X 
X 
X7 
X7 
X7 
X 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
X 
X11 
Vital Signs 
X1 
X1 
X1 
X1 
X1 
X1 
KPS 
X 
X 
X 
X 
X 
X 
ECG 
X2 
Radiographic 
Tumor 
Assessment 
of Chest/ 
Abd/ Pelvis 
X4 
X4 
X4 
CBC with 
Differential 
X 
X10 
X 
X 
X 
X 
Pregnancy Test 
(for patients 
of child 
bearing 
potential) 
X 
X 
Comprehensive 
Metabolic Panel 
X 
X10 
X 
X 
X 
X 
Coagulation 
Tests 
X 
Bone Density 
X 
Every 12 
months 
(±14 days) 
Tumor Biopsy 
X6, and 
IHC testing 
X6 
Dispense 
Onapristone ER 
(and anastrozole, 
if cohort 4) 
X8 
X8 
X8 
Chart review for 
PD 
Every 3 
months 
(±14 days) 
12 
Survival status 
Every 3 
months 
(±14 days) 
12 
 
1: Vital signs: blood pressure, heart rate, temperature and weight. Height need only be taken 
on Cycle 1, Day 1. 
2: Hypokalemia should be corrected prior to ECG collection 
3: All visits have a +/- 4 day window unless otherwise noted 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
4: Radiographic tumor assessment of abdomen and pelvis may be performed using CT or 
MRI.Chest imaging chould occur by CT. There is a +/- 7 day window for completion of 
interval tumor assessments by imaging. Imaging should be performed every 8 weeks 
following Day 1 of treatment. Radiographic tumor assessment at end of study treatment 
should only be completed for patients coming off study for reasons other than progression 
and only if it has been greater than 4 weeks since the last tumor assessment. 
5: End of Study Treatment Visit should happen within 30 days of last dose of study drug. 
6: Patients without adequate archival tissue from within the past 3 years available will have a 
biopsy performed, as medically appropriate for their disease. Patients who had progressive 
disease and consent for an end of treatment biopsy will have an optional non-billable tumor 
biopsy performed at end of treatment. 
7: Includes recording of concurrent medications and focused physical exam. There is a +/- 4 
day window allowable for each start of Cycle assessment. 
8: Pill diary and remaining pills should be collected and new pill diary and 1 month supply of 
study drug should be given to patient. Anastrozole will be prescribed by the treating 
physician and dispenced as commercial supply. 
9: Screening assessments should be completed within 30 days prior to treatment with the 
exception of CBC with differential, comprehensive metabolic panel, coagulation tests, and 
pregnancy test which should be completed within 14 days prior to treatment. 
10: Cycle 1 Day 1 blood tests can be omitted if Screening blood tests are completed within 
72 hours from Cycle 1 Day 1. 
11: A safety follow-up visit or phone call will be conducted 30 days (± 7 days) after the last 
dose of onapristone ER. AE should be monitored. 
12: Survival follow-up phone call will be conducted every 3 months from 30 day safety follow- 
up visit until the patient initiates a new treatment. 
For the patients who came off treatment due to unacceptable toxicity or withdrawal of 
consent, reviewing medical records for progression status will stop once the patient becomes 
POD. 
10.1 
Tumor Biopsy 
Tumor biopsies will potentially be performed at two time points during this study; a 
biopsy will be performed at screening if no archival tissue is available and an optional 
biopsy may be performed at end of treatment. 
If the patient has archival tissue available that is appropriate for PR IHC staining (block 
or unstained slides) or that has already had PR IHC completed, and is no more than 3 
years old, then archival tissue may be used. If ≥ 1% PR tumor staining is seen on ≥ 1 
slide the tumor will be considered to be PR+. 
 
An optional tumor biopsy will be performed at end of treatment in those patients who 
have POD, consent to biopsy, and have accessible disease. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
Biopsy samples should be fixed in 10% formalin and paraffin embedded. In cases 
where a reasonable size biopsy is obtained (i.e., excisional biopsy, 18 gauge 
needle), such that the pathologist feels there is adequate sample for preparation 
of both a frozen and fixed specimen, a fresh frozen biopsy should also be 
collected. At a minimum, enough tissue should be collected (by FNA or Core) for 
generation of a FFPE block for H&E and IHC analysis. At a maximum 2 cores should be 
collected. 
Lesions with the greatest change in dimensional size based on interval evaluation 
are the recommended lesions to be excised. Whenever possible, biopsies at POD 
should be performed within 3 days of study drug discontinuation. Biopsies obtained 
at the time of progressive disease will be used to investigate potential mechanisms 
of acquired resistance. Biopsy samples will be analyzed for level of PR positivity by 
IHC to determine if the progesterone receptor is downregulated during treatment with 
onapristone ER. 
10.2 Correlative Studies 
The degree of PR expression levels will be determined using standard 
immunohistochemistry methodology on all tissue and reported as percent tumor cells with 
PR staining. In cases where no PR results are available, one-three 5 micrometer superplus 
frost slides will be used for IHC testing. This testing will be performed at the Memorial Sloan 
Kettering Cancer Center CLIA approved clinical pathology laboratory using the Dako 
progesterone receptor antibody. Upon receipt of the slide in the clinical laboratory, results 
will be reported within 72 hours. The relationship between tumor response and degree of PR 
expression, and/or PR signaling, will be examined. 
 
Additional exploratory biomarkers will be evaluated on FFPE tissue , including 
phosphorylated PR and PR target gene expression. If ≥ 1% phosphorylated Ser294 PR 
(pPR) tumor staining is seen on ≥ 1 slide the tumor will be considered to be pPR+. Nuclear 
localization of pPR will also be evaluated. PR target gene analysis will be completed using 
the NanoString nCounter oncology panel system. NanoString analysis will require 25 ng of 
FFPE tissue. 
 
11.0 TOXICITIES/SIDE EFFECTS 
11.1 Toxicities to Date with ER Formulation: 
 
Under the Context therapeutics development program to date, 12 healthy female volunteers 
have received a single dose of 10 mg immediate release (IR) onapristone, 31 male patients 
with prostate cancer and 52 females with PR-positive breast, ovarian, and endometrial 
tumors have received doses of 10-50 mg onapristone ER BID or 100 mg/day of onapristone 
IR [[1-4]]. 
There were no grade 4 treatment-related AEs reported to date. The majority of adverse 
events were grade 1 or 2. Grade 3 adverse events were reported in 12 patients (16%) 
patients: GGT increase (5%), AP and AST increases (3% each), and nausea and anorexia 
(1% each). 
The most common related AEs reported (all grades) were asthenia (16%), GGT increase 
(15%), nausea (14%), AST increase (12%), and ALT increase (11%). Two patients 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
discontinued onapristone due to AEs. One patient discontinued due to three unrelated AEs 
(anemia, thrombocytopenia and leucopenia) in the context of bone marrow failure due to 
progressive bone metastases. The other patient had a 25% dose reduction for hepatic 
toxicity and subsequently discontinued onapristone due to disease progression/LFT 
abnormalities. 
One death has been reported within 30 days of discontinuing onapristone; respiratory 
distress due to progression of lung metastases. 
 
Common (>10%): nausea, asthenia, gamma glutamyltransferase increased 
 
Occasional (4-10%): abdominal distention, abdominal pain, diarrhea, dry mouth, fatigue, 
peripherial edema, pain, ALT and AST elevated, bilirubin increased, alkaline phosphate 
increased, LDH increased, LFT test abnormal, decreased appetite, hyperkalemia, 
tendonitis, agistation, hot flush, hypertension 
 
 
 
11.2 Potential for Drug-Drug Interaction: 
Data have suggested potential drug-drug interactions of onapristone with concomitantly 
administered CYP3A4 substrates and subsequent non-clinical studies have confirmed that 
onapristone interacts with midazolam, nifedipine and testosterone, demonstrating both 
induction and inhibition of CYP3A4, likely attributable to onapristone and its M2 metabolite. 
Therefore, until more data are available patients should be advised to avoid those agents 
which are sensitive substrates or strong inducers or inhibitors of CYP3A4 (see Table below). 
Patients will be instructed to avoid concomitant use of aspirin, NSAIDs, and prostaglandins. 
Intake of paracetamol up to 4 g/day dosed according to labeling is allowed. 
Caution should be exercised when onapristone is administered with drugs that are CYP3A4 
substrates and have narrow therapeutic range, including some agents used during general 
anesthesia. 
CYP3A Enzymes - Classification of Inhibitors 
 
CyP3A Inhibitors 
CyP3A Inducers 
CyP3A Substrates 
Strong 
Strong 
Sensitive 
Boceprevir 
Avasimibe 
Alfentanil 
clarithromycin 
carbamazepine 
Aprepitant 
conivaptan 
phenytoin 
Budesonide 
grapefruit juice 
rifampin 
buspirone 
indinavir 
St. John’s wort 
conivaptan 
itraconazole 
darifenacin 
ketoconazole 
darunavir 
lopinavir/ritonavir 
dasatinib 
mibefradil 
dronedarone 
nefazodone 
eletriptan 
nelfinavir 
eplerenone 
posaconazole 
everolimus 
ritonavir 
felodipine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
CyP3A Inhibitors 
CyP3A Inducers 
CyP3A Substrates 
saquinavir 
indinavir 
telaprevir 
fluticasone 
telithromycin 
lopinavir 
voriconazole 
lovastatin 
lurasidone 
Moderate 
Moderate 
maraviroc 
Amprenavir 
Bosentan 
midazolam 
aprepitant 
efavirenz 
nisoldipine 
atazanavir 
etravirine 
quetiapine 
ciprofloxacin 
modafinil 
saquinavir 
darunavir/ritonavir 
nafcillin 
sildenafil 
diltiazem 
simvastatin 
erythromycin 
sirolimus 
fluconazole 
tolvaptan 
fosamprenavir 
tipranavir 
grapefruit juice 
triazolam 
imatinib 
vardenafil 
verapamil 
Weak 
Weak 
Narrow therapeutic window 
Alprazolam 
Amprenavir 
Alfentanil 
amiodarone 
aprepitant 
astemizole 
amlodipine 
armodafinil 
cisapride 
atorvastatin 
echinacea 
cyclosporine 
bicalutamide 
pioglitazone 
dihydroergotamine 
cilostazol 
prednisone 
ergotamine 
cimetidine 
rufinamide 
fentanyl 
cyclosporine 
pimozide 
fluoxetine 
quinidine 
fluvoxamine 
sirolimus 
ginkgo 
tacrolimus 
goldenseal 
terfenadine 
isoniazid 
nilotinib 
oral contraceptives 
ranitidine 
ranolazine 
tipranavir/ritonavir 
zileuton 
FDA Guidance on Drug−Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL 
abeling/ucm080499.htm 
 
CYP3A Enzymes In vitro: 
 
CyP3A Inhibitors 
CyP3A Inducers 
CyP3A Substrates 
In vitro inhibitors 
In vitro inducers 
In vitro substrates 
ketoconazole 
rifampin 
midazolam 
itraconazole 
testosterone 
azamulin 
erythromycin 
troleandomycin 
dextromethorphan 
verapamil 
triazolam 4-hydroxylation 
terfenadine C-hydroxylation 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
CyP3A Inhibitors 
CyP3A Inducers 
CyP3A Substrates 
nifedipine oxidation 
FDA Guidance on Drug−Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL 
abeling/ucm080499.htm 
 
 
 
CYP3A Enzymes In vivo: 
 
In vivo inhibitors 
In vivo inducers 
In vivo substrates 
atazanavir 
rifampin 
midazolam 
clarithromycin 
carbamazepine 
buspirone 
indinavir 
felodipine 
itraconazole 
lovastatin 
ketoconazole 
eletriptan 
nefazodone 
sildenafil 
nelfinavir 
simvastatin 
ritonavir 
triazolam 
saquinavir 
telithromycin 
 
 
FDA Guidance on Drug−Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL 
abeling/ucm080499.htm 
 
11.3 Safety Measurements: 
 
Safety and tolerability will be determined by frequent assessment of adverse 
events, physical examinations, vital signs, and safety laboratory assessments as 
defined in section 10. A safety follow-up visit will be conducted 30 days (+/- 7 
days) after the last dose of onapristone ER. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria. 
12.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment on study. 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
disease re-evaluated will be considered evaluable for response. These patients will 
have their response classified according to the definitions stated below. (Note: 
Patients who exhibit objective disease progression prior to the end of cycle 1 will also 
be considered evaluable.) 
 
12.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 
clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless progression is documented or a biopsy is 
obtained to confirm persistence at least 90 days following completion of radiation 
therapy. 
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 recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed. 
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. Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non- 
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
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. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
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), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will 
be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions 
are not required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow-up. 
12.3 
Methods 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 unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) 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. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable. 
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. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., 
for body scans), but NOT lung. 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved in 
MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease. Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases. Ideally, the same type of scanner should 
be used and the image acquisition protocol should be followed as closely as possible 
to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. PET-CT scans are not always done with oral and IV contrast. In 
addition, the PET portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. For these reasons, we will not 
allow PET-CT use for RECIST 1.1 response criteria. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will 
be taken from one assessment to the next. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection is 
an endpoint. 
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). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
12.4 
Response Criteria 
12.4.1 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 the diameters of 
target lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: 
the appearance of one or more new lesions is also considered progressions). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
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. 
 
 
12.4.2 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). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
12.4.3 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 response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non- 
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
Study treatment will be discontinued for the following reasons: 
• Progression of disease (unless patient agrees to continue treatment 
past progression) 
• Persistent or unacceptable toxicity despite appropriate dose reductions 
• Withdrawal of consent 
• If in the opinion of the investigator continuation on study poses 
unreasonable risks to the patient. This might include patients who fail to 
return for adequate follow-up, hampering the ability to monitor toxicities 
 
Any patient discontinuing study drug should be seen at 30 days post discontinuation 
for the evaluations outlined in the study schedule. The patient’s tumor status should 
be assessed clinically and, if appropriate, disease progression should be confirmed 
by radiological assessment. 
After discontinuation of the study medication at any point in the study, all ongoing AEs 
or SAEs must be followed until resolution unless, in the investigator’s opinion the 
condition is unlikely to resolve due to the patients underlying disease, or the patient is 
lost to follow up. All new AEs and SAEs occurring during the 30 calendar days after the 
last dose of study medication must be recorded, reported if applicable and followed to 
resolution as above. Patients should be contacted at least 30 days after discontinuing 
study medication to collect and /or complete AE information. Any untoward event 
occurring subsequent to the 30-day follow-up AE reporting period that the investigator 
assesses as possibly related to the study medication should also be reported as an AE. 
Any patient, who has not yet shown objective disease progression, should continue to 
be followed as per RECIST 1.1. 
 
The study and/or individual Cohorts may be discontinued if it is found that it is not 
feasible to reach the planned outcomes. 
13.1 Treatment Past Progression: 
 
If a patient is found to have progression of disease by RECIST 1.1 criteria, but in the 
opinion of the treating clinician is felt to potentially still derive benefit, after discussion 
with study PI, the patient may consent to continue with protocol directed treatment. If 
the patient decides to continue receiving treatment, the patient will be asked to sign a 
separate consent form. The treating clinicans discussion of treatment past 
progression with the patient should be documented in the medical record. 
 
 
14.0 
BIOSTATISTICS 
This is a single institution, investigator initiated, open label, basket study exploring the efficacy of 
onapristone ER in PR+ recurrent or advanced gynecologic cancer that has been designed as three 
parallel Simon 2-Stage studies testing the recommended phase 2 dose of onapristone ER as a 
single agent or in combination with anastrozole in histologies of interest. 
Three histologies of interest are being examined: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
Cohort 1: Granulosa cell ovarian cancer (onapristone single agent) 
Cohort 2: Low grade serous ovarian cancer (onapristone single agent) 
Cohort 3: Endometrioid endometrial cancer (onapristone single agent) 
Cohort 4: Granulosa cell ovarian cancer (onapristone in combination with anastrozole) 
The null hypothesis for each basket is based on poor historical rates to systemic therapies in these 
histologies. While prospective data is lacking in patients with low grade serous ovarian cancer the 
retrospective response rate to chemotherapy is 4%, and 9% to available hormonal therapies [7, 8, 
12, 13]. Granulosa cell, the most common type of sex-cord stromal ovarian cancer, generally has 
poor response rates to chemotherapy and is commonly treated with hormonal strategies, most 
commonly aromatase inhibitors, though the response rate to anastrozole in recurrent granulosa cell 
tumors is 2.5%. [9]. Endometrial cancer also has limited options with a 13% response rate to 
chemotherapy in the second line [10]. Megestrol acetate is the only systemic treatment FDA 
approved specifically for endometrial cancer and has shown response rates as high as 24% in 
conjunction with tamoxifen in the recurrent setting, but is not commonly used due to poor tolerance 
[11]. Tamoxifen as a single agent has a response rate of 10% in recurrent endometrial cancer[14, 
15] . 
A short-coming of this design is that a basket study which implements multiple independent two- 
stage designs has a higher overall false-positive rate than a typical phase II study[16]. However, to 
modulate this effect we have limited this study to 4 baskets/cohorts. Sample size calculations are 
based on the Simon two-stage minimax design. 
For Cohort 1 if ≥ 1/14 complete or partial responses are seen by RECIST 1.1 criteria within 6 months 
of treatment (stage I) then the study will expand to stage II. If a total of ≥ 3/23 responses (inclusive of 
the original 14 patients from stage I) are seen then this Cohort will be deemed worthy of further 
investigation. This assumes an unacceptable response rate of 3% and a desirable response rate of 
20% with a Type I error rate of 5% and a Type II error rate of 15%. 
For Cohort 2 if ≥ 2/16 complete or partial responses are seen by RECIST 1.1 criteria within 6 months 
of treatment (stage I) then the study will expand to stage II. If a total of ≥ 5/25 responses (inclusive of 
the original 16 patients from stage I) are seen then this Cohort will be deemed worthy of further 
investigation. This assumes an unacceptable response rate of 10% and a desirable response rate of 
30% with a Type I error rate of 10% and a Type II error rate of 10%. 
For Cohort 3 if ≥ 4/19 complete or partial responses are seen by RECIST 1.1 criteria within 6 months 
of treatment (stage I) then the study will expand to stage II. If a total of ≥ 11/36 responses (inclusive 
of the original 19 patients from stage I) are seen then this Cohort will be deemed worthy of further 
investigation. This assumes an unacceptable response rate of 20% and a desirable response rate of 
40% with a Type I error rate of 10% and a Type II error rate of 10%. 
For Cohort 4 if ≥ 1/14 complete or partial responses are seen by RECIST 1.1 criteria within 6 months 
of treatment (stage I), then the study will expand to stage II. If a total of ≥ 3/23 responses (inclusive 
of the original 14 patients from stage I) are seen then this Cohort will be deemed worthy of further 
investigation. This assumes an unacceptable response rate of 3% and a desirable response rate of 
20% with a Type I error rate of 5% and a Type II error rate of 15%. 
Secondary/Exploratory objectives: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
To evaluate the safety and tolerability of onapristone ER alone or in combination with anastrozole in 
these patient populations toxicity data will be collected at each visit and tabulated with grading by 
CTCAE Version 5 criteria. Dose holding and modifications will occur as described in section 9.2 
The objective response rate and progression free survival (PFS) will be analyzed separately for each 
disease type (basket/cohort 1,2,3 and4). PFS will be defined from the start of treatment to disease 
progression or death (whichever occurs first) or last follow-up. Kaplan Meier estimates will be used 
to estimate the median PFS and 2-year rate. Response will be determined by RECIST 1.1 criteria. 
Objective response is defined as complete or partial response by week 36 or best overall response. 
Duration of response will be reported for the subset of patients who experience an objective 
response.Clinical Benefit Rate (CBR) is defined as the percentage of patients who have achieved a 
complete response, partial response, or stable disease lasting ≥ 16 weeks. 
Patients coming off study prior to first post-baseline assessment for reasons other than toxicity or 
progression may be replaced following discussion with study PI, if deemed appropriate. Patients 
who have measurable disease present at baseline, have received at least one cycle of therapy, 
and have had their disease re-evaluated will be considered evaluable for response Accrual in 
each cohort will continue until the required number of evaluable patients in each cohort are accrued. 
Responses will be confirmed by repeat imaging performed at least 4 weeks after confirmed 
response. Binomial proportions will be assumed when calculating the 2 sided 80% confidence 
interval around the objective response rate for each cohort separately. 
To correlate the level of PR positivity (measured by immunohistochemsirty as a continuous 
variable), the level of phosphorylated PR (as a continuous variable) and the level of PR target gene 
expression (as a continuous variable) with response to therapy (defined as complete or partial 
response by week 36) with onapristone ER, a non-parametric test, such as the Wilcoxon test, will be 
used to test whether the PR levels (continuous variable) are different in the 2 groups of responders 
(complete or partial response) vs non responders. Each cohort/basket will be analyzed separately. 
Sample Size: 
Cohort 1 has enrolled 14 patients and stopped at Stage 1. Cohorts 2 (5 patinets enrolled) and 3 (1 
patient enrolled) closed early due to poor accrual. Cohort 4 will enroll 14-23 patients.This study is 
expected to enroll between 34 and 43patients. Accrual of 1-2 patients per month is anticipated. The 
study is expected to complete accrual within 12- 24 months. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
 
15.2 
Randomization 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
This is a non-randomized study 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
 
 
16.0 
DATA MANAGEMENT ISSUES 
A Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities of 
the CRC include data collection, abstraction and entry, data reporting, and problem 
resolution and prioritization. 
The data collected for this study will be entered into Medidata, a secure database. Source 
documentation will be available to support the computerized patient record. 
The estimated rate of accrual will be 1-2 patients per month. All patients will remain on 
treatment until POD, intolerable toxicity, self-discontinuation of study treatment, or removal 
from study for any other reason. 
16.1 
Quality Assurance 
Registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow- 
up will be monitored periodically throughout the study period and potential problems 
will be brought to the attention of the study team for discussion and action 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled ―Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials‖ which can be 
found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM 
Plans at MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Clinical Research 
Portal. 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center‘s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
17.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified researchers. 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
 
• 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate, the report will be forwarded to the FDA by the IND Office 
 
17.2.1 
All SAEs need to be reported to the Context Therapeutics within 5 days of notification of the 
event. The MSK SAE form should be sent to: 
Tarek Sahmoud, MD, PhD 
Chief Medical Officer 
Context Therapeutics 
P: (267) 454-8755 
E: tsahmoud@contexttherapeutics.com 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 19-061 A(9) 
Approval date: 24-Apr-2023 
 
19.0 
REFERENCES 
1. 
Keyvan Rezai, e.a., A single-dose PK study of onapristone including the effect of food on 
absorption. Cancer Chemotherapy and Pharmacology 76(1), May 2015: p. 171-177. 
2. 
Anuradha Jayaram, e.a., Phase 1-2 study of progesterone receptor (PR) inhibition with 
extended-release (ER) onapristone (ONA) alone or in combination with abiraterone (AA) in 
patients (pts) with castration-resistant prostate cancer (CRPC) incorporating plasma DNA 
analysis to def. Annals of Oncology, October 13, 2017: p. Volume 28, Issue suppl_7, 1 
October 2017. 
3. 
Paul Cottu, e.a., Phase I Study of Onapristone, a Type I Antiprogestin, in Female Patients 
with. PLOS One, 2018: p. Online. 
4. 
Rezai, K., et al., A single-dose PK study of onapristone including the effect of food on 
absorption. Cancer Chemother Pharmacol, 2015. 76(1): p. 171-7. 
5. 
Jonat, W., Giurescu, M., Robertson, JFR. , The Clinical Efficacy of Progesterone Antagonists 
in Breast Cancer. Endocrine Therapy of Breast Cancer. . 2002. 
6. 
Robertson, J.F., et al., Onapristone, a progesterone receptor antagonist, as first-line therapy 
in primary breast cancer. Eur J Cancer, 1999. 35(2): p. 214-8. 
7. 
Gershenson, D.M., et al., Hormonal therapy for recurrent low-grade serous carcinoma of the 
ovary or peritoneum. Gynecol Oncol, 2012. 125(3): p. 661-6. 
8. 
Gershenson, D.M., et al., Recurrent low-grade serous ovarian carcinoma is relatively 
chemoresistant. Gynecol Oncol, 2009. 114(1): p. 48-52. 
9. 
Banerjee, S., Tang, M., O'connell, R, Clamp, A., Lord, R., Mullassery, V.M., Hall, M., 
Gourley, C., Bonaventura, T., Goh, J., Sykes, P., Grant, P.T., McNally, O., Edmondson, R.J., 
Friedlander, M., PARAGON: A phase 2 study of anastrazole in patients with estrogen 
receptor/ and progesterone receptor positive recurrent/metastatic granulosa cell tumors/sex- 
cord stromal tumors of the ovary J Clin Oncol, 2018. 36(suppl; abstr 5524). 
10. 
Miller, D., Scambia, G., Bondarenko, I., Westermann, A., Oaknin, A., Oza, A., Sergeevua, A., 
Vergote, I., Wenham, R.M., Temkin, S., Gabra, H., ZoptEC: Phase III randomized controlled 
study comparing zoptarelin with doxorubicin as second line therapy for locally advanced, 
recurrent, or metastatic endometrial cancer. J Clin Oncol, 2018. 36(suppl; abstr 5503). 
11. 
Fiorica, J.V., et al., Phase II trial of alternating courses of megestrol acetate and tamoxifen in 
advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol, 
2004. 92(1): p. 10-4. 
12. 
Grisham, R.N. and G. Iyer, Low-Grade Serous Ovarian Cancer: Current Treatment 
Paradigms and Future Directions. Curr Treat Options Oncol, 2018. 19(11): p. 54. 
13. 
Gershenson, D.M., Low-grade serous carcinoma of the ovary or peritoneum. Ann Oncol, 
2016. 27 Suppl 1: p. i45-i49. 
14. 
Thigpen, T., et al., Tamoxifen in the treatment of advanced or recurrent endometrial 
carcinoma: a Gynecologic Oncology Group study. J Clin Oncol, 2001. 19(2): p. 364-7. 
15. 
Battista, M.J. and M. Schmidt, Fulvestrant for the treatment of endometrial cancer. Expert 
Opin Investig Drugs, 2016. 25(4): p. 475-83. 
16. 
Cunanan, K.M., et al., Basket Trials in Oncology: A Trade-Off Between Complexity and 
Efficiency. J Clin Oncol, 2017. 35(3): p. 271-273. 
 
20.0 
APPENDICES 
Appendix A: Pill Diary 
Appendix B: KPS Scale 
Appendix C: Radiation Dosimetry