Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer receiving gemcitabine (gemcitabine hydrochloride) in combination with AZD 1775 (MK-1775 \[WEE1 inhibitor MK-1775\]) compared to subjects receiving gemcitabine in combination with placebo.

SECONDARY OBJECTIVES:

I. To evaluate the objective response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of patients receiving gemcitabine combined with AZD 1775 (MK-1775) compared to patients receiving gemcitabine in combination with placebo.

II. To evaluate the Gynecologic Cancer Intergroup (GCIG) cancer antigen (CA)125 response rate of patients receiving gemcitabine combined with AZD 1775 (MK-1775) compared to patients receiving gemcitabine in combination with placebo.

III. To evaluate the overall survival of patients (max 1-year \[yr\] follow-up) receiving gemcitabine combined with AZD 1775 (MK-1775) compared to patients receiving gemcitabine in combination with placebo.

IV. To evaluate the safety and tolerability of the combination of gemcitabine combined with AZD 1775 (MK-1775) in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.

V. To evaluate tumor protein p53 (TP53) mutations (presence of mutation and type of mutation) as potential predictive factors of benefit (defined as response or progression-free survival \[PFS\] prolongation) to AZD 1775 (MK-1775) and gemcitabine treatment.

VI. To evaluate p53 protein expression by immunohistochemistry as potential predictive factors of benefit (defined as response or PFS prolongation) to AZD 1775 (MK-1775) and gemcitabine treatment.

TERTIARY OBJECTIVES:

I. To evaluate patient reported outcomes using Patient-Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE).

II. To evaluate the concordance of TP53 mutations in the tumor specimen and TP53 mutations determined by tagged-amplicon deep sequencing (Tam-Seq) in circulating tumor DNA.

III. To correlate the levels circulating DNA TP53 mutations by Tam-Seq with response.

IV. Validation of phosphorylated-cyclin-dependent cycle 2 (pCDC2) and gamma-H2A histone family, member X (H2AX) in skin and tumor tissue as a pharmacodynamic marker of therapy.

V. To correlate changes in pCDC2 and gamma-H2AX with survival outcomes and response rate.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive WEE1 inhibitor MK-1775 orally (PO) on days 1, 2, 8, 9, 15, and 16 and gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO on days 1, 2, 8, 9, 15, and 16 and gemcitabine hydrochloride as patients in Arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-8 weeks (after the 30-37 day safety visit) for up to 1 year.

• Adavosertib (Drug), also known as AZD 1775, AZD-1775, AZD1775, MK 1775, MK-1775, MK1775: Given PO
• Gemcitabine Hydrochloride (Drug), also known as dFdCyd, Difluorodeoxycytidine Hydrochloride, Gemcitabine HCI, Gemzar, LY 188011, LY-188011, LY188011: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies
• Pharmacological Study (Other): Correlative studies
• Placebo Administration (Other): Given PO
• Questionnaire Administration (Other): Ancillary studies

Primary outcomes

• Progression Free Survival [From start of treatment until date of progression or death, whichever occurs first, up to 1 year follow-up]: To evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer receiving gemcitabine in combination with AZD1775 compared to subjects receiving gemcitabine in combination with placebo. Progression is defined, using the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guideline, as at least a 20% increase in the sum of the diameters of target lesions or the appearance of one or more new lesions.

Secondary outcomes

• Objective Response [From start of treatment, every 6-8 weeks, until time of progression or death, whichever occurs first, up to 1 year follow-up]: To evaluate the objective response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) of patients receiving gemcitabine combined with AZD1775 compared to patients receiving gemcitabine in combination with placebo. RECIST v1.1 criteria used for evaluation of target lesions: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the diameters of target lesions; Progressive Disease (PD), at least a 20% increase in the sum of the diameters of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. The Best Overall Response is the best response recorded from the start of the treatment until disease progression/recurrence .
• Response According to CA125 Criteria [From start of treatment, every 4 weeks, until time of progression or death, whichever occurs first, up to 1 year follow-up]: To evaluate the GCIG CA125 response rate of patients receiving gemcitabine combined with AZD1775 compared to patients receiving gemcitabine in combination with placebo. A response according to CA-125 has occurred if there is at least a 50% reduction in CA-125 levels from a pre-treatment sample. The response must be confirmed and maintained for at least 28 days.
• Overall Survival [From start of study treatment, every 12 weeks, until death, up to 22 months follow-up]: To evaluate the overall survival of patients receiving gemcitabine combined with AZD1775 compared to patients receiving gemcitabine in combination with placebo.
• Number of Participants With Grade 3 or 4 Adverse Events Related to Study Treatment [From start of treatment until AE resolution, stabilization, or improvement to less than grade 2, up to 1 year follow-up]: To evaluate the safety and tolerability of the combination of gemcitabine combined with AZD1775 in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.
• TP53 Mutations [Baseline]: To evaluate TP53 mutations (presence of mutation and type of mutation) as potential predictive factors of benefit (defined as response or PFS prolongation) to AZD1775 and gemcitabine treatment. TP53 status was assessed using Sanger sequencing.
• p53 Protein Expression [Baseline]: To evaluate p53 protein expression by immunohistochemistry as potential predictive factors of benefit (defined as response or PFS prolongation) to AZD1775 and gemcitabine treatment. Evaluating p53 expression in patients with high-grade serous ovarian cancer and in patients with high-grade serous ovarian cancer with TP53 mutations.

Other outcomes

• Patient Reported Outcomes [First 3 months]: Will be assessed using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). Each symptomatic AE is assessed with respect to 1 to 3 of the following attributes: frequency (F), severity (S) and/or interference (I) with usual or daily activities, and a recall period of 'the past 7 days'. PRO-CTCAE responses are scored from 0 to 4 with scores of 3 and 4 corresponding to high frequency, severity and/or interference. Results show the number of patients in each arm reporting high scores (3-4) for symptomatic AEs occurring in >30% of patients
• TP53 Mutations in Circulating Tumor Deoxyribonucleic Acid [Baseline]: TP53 mutations in circulating tumor deoxyribonucleic acid will be evaluated by TAm-Seq.
• Change in Levels of Circulating Deoxyribonucleic Acid TP53 Mutations by TAm-Seq [Baseline to up to 1 year]: Levels of circulating deoxyribonucleic acid TP53 mutations will be correlated with response. *No results for this outcome measure
• Changes in pCDC2 in Skin and Tumor Tissue [Baseline and at day 2 or 9 (course 1)]: Validation of pCDC2 as a pharmacodynamic marker of therapy. *No results for this outcome measure
• Changes in gH2AX in Skin and Tumor Tissue [Baseline and at day 2 or 9 (course 1)]: Validation of gH2AX as a pharmacodynamic marker of therapy. *No results for this outcome measure
• Changes in pCDC2 [Baseline and at day 2 or 9 (course 1)]: Changes in pCDC2 will be correlated with survival outcomes and response rate. *No results for this outcome measure
• Changes in pH2AX [Baseline and at day 2 or 9 (course 1)]: Changes in pH2AX will be correlated with survival outcomes and response rate. *No results for this outcome measure

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed epithelial ovarian, primary peritoneal and fallopian tube carcinoma; all histologic subtypes of epithelial ovarian cancer are eligible, but only patients with high grade serous ovarian cancer will be considered for the statistical analysis; non-high grade serous cancers will be allowed in an exploratory cohort
* Patients must be platinum-resistant (platinum-free interval < 6 months) or have platinum-refractory disease as per Gynecologic Cancer Intergroup Committee (GCIC) criteria; disease progression has to be radiologic or clinical; biomarker progression with CA125 after a platinum based regimen would not be sufficient evidence of disease progression; the patients must have had radiological progression to that regimen
* Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 10 mm with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
* There is no limitation in the number of prior lines of therapy
* Patients must have completed any prior chemotherapy, radiotherapy or major surgery at least 4 weeks before receiving study treatment; ongoing toxicities related to treatment must be =< grade 1 and patients with grade 2 alopecia or peripheral neuropathy can also be included; palliative radiation to < 10% of bone marrow is permissible if completed within one week of commencing study treatment as long as the toxicities secondary to palliative radiotherapy are limited to grade 1; the lesions that have received radiation treatment immediately before will be excluded as target lesions; previously irradiated lesions can be considered as targeted lesions, as long as there is prove of radiological progression
* Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
* Life expectancy of greater than 3 months
* Leukocytes >= 3,000/mcL
* Absolute neutrophil count >= 1,500/mcL
* Platelets >= 100,000/mcL
* Hemoglobin >= 90 g/L

  * Blood transfusions are allowed at any time during the screening, treatment or follow-up period, according to the center recommendations
* Prothrombin time (PT), partial thromboplastin time (PTT) and international normalized ratio (INR) =< 1.5 upper limit of normal (ULN)
* Total bilirubin =< 1.5 x institutional upper limit of normal; unless due to Gilbert's syndrome
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =< 3 x institutional upper limit of normal (5 x if liver metastases)
* Creatinine =< 1.5 × institutional upper limit of normal OR creatinine clearance >= 40 mL/min/1.73 m\^2 for patients with creatinine levels above 1.5 x institutional limit of normal
* Patients must be able to tolerate oral medication and not have evidence of active bowel obstruction

  * Note: patients can have a history of prior bowel obstruction, provided the patient is not having symptoms of bowel obstruction at the time of enrolment and the bowel obstruction is not anticipated to recur during the participation in the study
* Patients must have disease amenable to biopsy and must be willing to undergo a paired biopsy for correlative analyses (the first biopsy within 28 days prior to start of treatment and the second biopsy while on treatment)
* Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

  * Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible reason
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients who previously received gemcitabine for the treatment of recurrent disease
* Patients who are receiving any other investigational agents
* Patients with clinically or radiologically unstable brain metastases are excluded from this clinical trial

  * Note: patients with stable brain metastases after treatment, for at least 3 months prior to enrolling on this trial, could participate in the study; patients should be off, or on a stable dose of steroids
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD 1775 (MK-1775) or gemcitabine
* Patients taking the following prescription or non-prescription drugs or other products (i.e. grapefruit juice) are ineligible: sensitive cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrates, CYP3A4 substrates with a narrow therapeutic index, moderate to potent inhibitors/inducers of CYP3A4; patients would be eligible if the medications can be discontinued two weeks prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication
* Pregnant and breastfeeding women are excluded from this study
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
* Uncontrolled intercurrent illness including, but not limited to, myocardial infarction within 6 months, congestive heart failure, symptomatic congestive heart failure, unstable angina pectoris, active cardiomyopathy, unstable ventricular arrhythmia, uncontrolled hypertension, uncontrolled psychotic disorders, serious infections, active peptic ulcer disease, active liver disease or cerebrovascular disease with previous stroke, or psychiatric illness/social situations that would limit compliance with study requirements

Participant flow

Outcome results

• Progression Free Survival (Primary), Median, months: Arm I (WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 4.6 (3.6 to 6.4); Arm II (Placebo, Gemcitabine Hydrochloride) 3.0 (1.8 to 3.8); Arm III (Exploratory WEE1 Inhibitor AZD1775, Gemcitabine) 5.3 (1.6 to 7.7)
• Objective Response (Secondary), Count of participants, Participants: Arm I (WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 14; Arm II (Placebo, Gemcitabine Hydrochloride) 2; Arm III (Exploratory WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 3
• Response According to CA125 Criteria (Secondary), Count of participants, Participants: Arm I (WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 14; Arm II (Placebo, Gemcitabine Hydrochloride) 3; Arm III (Exploratory WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 4
• Overall Survival (Secondary), Median, months: Arm I (WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 11.4 (8.2 to 16.5); Arm II (Placebo, Gemcitabine Hydrochloride) 7.2 (5.2 to 13.2); Arm III (Exploratory WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 13 (8.5 to 21.7)
• Number of Participants With Grade 3 or 4 Adverse Events Related to Study Treatment (Secondary), Count of participants, Participants: Arm I (WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 38; Arm II (Placebo, Gemcitabine Hydrochloride) 10; Arm III (Exploratory WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 18
• TP53 Mutations (Secondary), Count of participants, Participants: Arm I (WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 48; Arm II (Placebo, Gemcitabine Hydrochloride) 22; Arm III (Exploratory WEE1 Inhibitor AZD1775, Gemcitabine Hydrochloride) 8
• p53 Protein Expression (Secondary), Count of participants, Participants: Abnormal p53 Expression in Patients With High-grade Serous Ovarian Cancer 82; Abnormal p53 Expression in Patients With High-grade Serous Ovarian Cancer and With TP53 Mutations 68
• Patient Reported Outcomes (Other pre specified), Count of participants, Participants: Arm I (WEE1 Inhibitor AZD-1775, Gemcitabine Hydrochloride) 10; Arm II (Placebo, Gemcitabine Hydrochloride) 9; Arm III (Exploratory WEE1 Inhibitor AZD-1775, Gemcitabine) 1
• TP53 Mutations in Circulating Tumor Deoxyribonucleic Acid (Other pre specified)
• Change in Levels of Circulating Deoxyribonucleic Acid TP53 Mutations by TAm-Seq (Other pre specified)
• Changes in pCDC2 in Skin and Tumor Tissue (Other pre specified)
• Changes in gH2AX in Skin and Tumor Tissue (Other pre specified)
• Changes in pCDC2 (Other pre specified)
• Changes in pH2AX (Other pre specified)

Adverse events

Time frame: Adverse Events monitored/assessed from start of treatment until AE resolution, up to 1 year follow-up. All-Cause Mortality monitored/assessed for up to 22 months.

Serious adverse events by term

Other adverse events by term

67 more terms not shown.

Limitations and caveats: * Randomization in a 2:1 ratio is associated with reduced statistical power - increased the sample size by 12% compared to a 1:1 randomization design * No stratification factors because of the small sample size, potentially resulting in imbalances in BRCA mutation status * Absence of quality-of-life assessment

• Results publication: Lheureux S, Cristea MC, Bruce JP, Garg S, Cabanero M, Mantia-Smaldone G, Olawaiye AB, Ellard SL, Weberpals JI, Wahner Hendrickson AE, Fleming GF, Welch S, Dhani NC, Stockley T, Rath P, Karakasis K, Jones GN, Jenkins S, Rodriguez-Canales J, Tracy M, Tan Q, Bowering V, Udagani S, Wang L, Kunos CA, Chen E, Pugh TJ, Oza AM. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 Jan 23;397(10271):281-292. doi: 10.1016/S0140-6736(20)32554-X. PMID 33485453

• Study Protocol and Statistical Analysis Plan (PDF, 2019-01-03)

• Amit M Oza, Principal investigator, University Health Network-Princess Margaret Hospital

NIH grants: N01CM00032, N01CM00038, N01CM00071, U10CA180821, UM1CA186644, UM1CA186705