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All Drugs and Chemicals

Prexasertib

Protein Kinase Inhibitors

Enzyme Inhibitors

Prexasertib (LY2606368) monotherapy treatment

105 mg/m\^2 intravenous (IV) once every 14 days of a 28 day cycle

LY2606368

Jung-Min Lee, M.D.

Background:

* All cells go through cycles which allow them to divide. In normal cells, checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) (CHEK 2 (Chk1/2) stop cell division at various points to allow any damage to deoxyribonucleic acid (DNA) to be repaired.
* When Chk1/2 are not present, cells stop dividing and eventually die. Chk1/2 Inhibitor (Prexasertib (LY2606368) blocks the Chk1/2 proteins.
* Researchers hope that by blocking Chk1/2, it will cause tumor cells to die, thereby shrinking tumors.

Objective:

- To see if LY2606368 helps shrink tumors in patients with certain breast, ovarian or prostate cancers.

Eligibility:

- Participants at least 18 years old with breast or ovarian cancer. They must have a mutation in BRCA1 BReast CAncer gene 1 and BRCA2 BReast CAncer gene 2 (BRCA1/2) genes for group 1, high grade serious ovarian cancer without BRCA1/2 mutation for group 2, or triple negative breast cancer without BRCA1/2 mutation for group 3, or prostate cancer with or without BRCA1/2 mutation for group 4.

Design:

* Participants will be screened with a medical history and physical exam. They will have blood tests, an electrocardiogram (ECG) heart test, scans, and X-rays. They will have a piece of their tumor removed at entry (computed tomography (CT)-assisted biopsy).
* Study Day 1: Participants will have a physical exam and blood drawn. They may have a CT scan of the chest, abdomen, and pelvis.
* Day 1 and Day 15 of each 28-day cycle: Participants will receive the study drug through an intravenous (IV).
* Vital signs will be checked before and after. An ECG will be done within 1 hour after.
* Day 15 and Day 28: Participants will have a physical exam, blood drawn, and a 12 lead ECG.
* Cycle 1: Participants will have weekly phone calls and blood draws. Participants may have another CT-assisted biopsy at the end of cycle 1.
* Cycle 2 and beyond, blood will be drawn every other week for routine blood tests.
* Participants will have an after-study visit with a physical exam and blood tests. Participants may have another biopsy when they progressed on treatment. They will have scans of the chest, pelvis, and abdomen and a 12 lead ECG.

Background:

* Checkpoint kinases 1 and 2 (Chk1/2) are major regulators of the cell cycle and are intimately associated with the cellular response to deoxyribonucleic acid (DNA) damage and repair. Chk1/2 also function as the primary mediators of cell cycle arrest in tumors with tumor protein P53 (p53) dysfunction, such as high-grade serous ovarian cancer (HGSOC), and triple negative breast cancer (TNBC).
* Participants with germline BRCA1 BReast CAncer gene 1 and BRCA2 BReast CAncer gene 2 (BRCA1/2) mutation have inherent defects in DNA damage repair pathways.
* Chk1/2 inhibition alone yielded DNA damage and mitotic catastrophe preclinically, even in the absence of DNA damage by external agents in tumors with underlying DNA repair dysfunction.
* The second-generation Chk1/2 inhibitor (Prexasertib (LY2606368) yielded safety and preliminary single agent activity in advanced cancer participants.
* We hypothesize that LY2606368 will result in clinical benefit in participants with Germline BRCA-Mutated (gBRCAm)-associated breast or ovarian cancers, and HGSOC and TNBC with low genetic risk.

Objectives:

* To determine the objective response rate (Complete Response (CR)+Partial Response (PR) of single agent LY2606368 in patients with gBRCAm-associated breast or ovarian cancer, HGSOC and TNBC with low genetic risk.
* To determine the safety and toxicity, and progression-free interval (PFI) of LY2606368 in pretreated participants.
* To determine biochemical changes in the DNA damage repair and cell cycle check point pathways in tumor and blood samples in response to treatment.
* To determine potential resistance mechanisms to LY2606368 treatment in HGSOC.

Eligibility:

* Participants with recurrent/refractory BReast CAncer gene (BRCA) mutant breast or ovarian cancer, HGSOC, and TNBC, for whom there remains no standard curative measures.
* A documented deleterious germline or somatic BRCA mutation for breast or ovarian cancer participants enrolling in Cohort 1.
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for HGSOC (Cohort 2).
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for TNBC (Cohort 3).
* Effective with amendment I (version date 4/24/2017), Metastatic Castration-Resistant Prostate Cancer (mCRPC), Cohort 4 was closed.
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for recurrent platinum-resistant HGSOC with measurable and biopsiable disease (Cohort 5).
* Negative BRCA mutation testing or negative family history of hereditary breast and ovarian cancer syndrome for recurrent platinum-resistant HGSOC with measurable but without biopsiable disease (Cohort 6).
* Participants must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and adequate organ and marrow function.

Design:

* This is an open label, single arm phase II trial to examine activity of LY2606368 in participants in the 6 independent cohorts (Cohorts 1-6).
* LY2606368 will be dosed at the recommended phase 2 dose (RP2D) of 105 mg/m\^2 intravenous (IV) once every 14 days of a 28 day-cycle.
* Research samples including whole blood, circulating tumor cells (CTCs), and tumor biopsies will be obtained for pharmacodynamics (PD) endpoints at baseline, Cycle 1 Day 15 (6-24hour (hr) post-2nd dose), and/or at progression in all participants. Tumor biopsies will not be performed in Cohort 6.
* Participants (Cohorts 1-3, 5 and 6) will be evaluated every two cycles for response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and every cycle for safety using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer

A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) In BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, and High Grade Serous Ovarian Cancer

For All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

In addition, all large-scale genomic sequencing data will be shared with subscribers to database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Objective response (CR+PR) of single agent Prexasertib (LY2606368) in participants with germline BReast CAncer gene -Mutated (gBRCAm)-associated breast and ovarian cancers, high grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) at low genetic risk. Response was measured using the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response is disappearance of all target lesions. Partial Response is at least a 30% decrease in the sum of diameters of target lesions.

National Cancer Institute (NCI)

Principal Investigator

Cohorts 5 \& 6 are combined because they are for platinum resistant BRCA wild type high grade serous ovarian cancer (HGSOC) participants, literally the same population. Only difference between the two cohorts is cohort 5 is a research biopsy cohort \&cohort 6 had no safely biopsiable disease. Given that Eli Lilly prematurely terminated the study we could not enroll enough number of participants for both cohorts. Thus, it is appropriate and scientifically relevant to report the data in one group.

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1.

Cohort 1 Breast/Ovarian Breast Cancer (BRCA) Mutation Positive

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except six participants who received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And one participant did not receive drug.

Cohort 2 Breast/Ovarian Breast Cancer (BRCA) Wild-Type (wt) Cohort

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except two participants who received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Cohort 3 Breast Cancer (BRCA) Wild-Type (wt) Triple Negative Breast Cancer

One participant received Prexasertib (LY2606368) 105 mg/m\^2 on dose level -1 followed by Prexasertib 80 mg/m\^2 on dose level -1. And one participant received Prexasertib 105 mg/m\^2 on dose level 1.

Cohort 4 Castration-resistant Metastatic Prostate

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except six participants in cohort 5 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And three participants on cohort 6 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Cohorts 5 and 6 Ovarian Breast Cancer (BRCA) Wild-Type (wt) Platinum-resistant

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Cohorts 5 \& 6 are combined because they are for platinum resistant BRCA wild type high grade serous ovarian cancer (HGSOC) participants, literally the same population. Only difference between the two cohorts is cohort 5 is a research biopsy cohort \& cohort 6 had no safely biopsiable disease. Given that Eli Lilly prematurely terminated the study we could not enroll enough number of participants for both cohorts. Thus, it is appropriate and scientifically relevant to report the data in one group.

Dr. Jung-min Lee

Complete Response

Partial Response

Cohorts 5 and 6 are combined because they are for platinum resistant BRCA wild type high grade serous ovarian cancer (HGSOC) participants, literally the same population. Only difference between the two cohorts is cohort 5 is a research biopsy cohort and cohort 6 had no safely biopsiable disease. Given that Eli Lilly prematurely terminated the study we could not enroll enough number of participants for both cohorts.

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except six participants in cohort 5 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And three participants on cohort 6 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Overall, 17 participants were not evaluable for this outcome measure. Overall participants analyzed adjusted to include only evaluable subjects as defined by the protocol (i.e., only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated; Response Evaluation Criteria in Solid Tumors (RECIST) Evaluable).

Objective Response (Complete Response (CR) + Partial Response (PR)

All participants received Prexasertib (LY2606368) 105 mg/m\^2 on dose level 1, except four participants in cohort 5 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1. And one participant on cohort 6 received Prexasertib 105 mg/m\^2 on dose level 1 followed by 80 mg/m\^2 on dose level -1.

Cohorts 5 and 6 Breast Cancer (BRCA) Wild-Type (wt) Platinum Resistant Cohort

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

Overall Study

Blood and Lymph Conditions

Immune System Diseases

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Antineoplastic Agents

Amino Acids

Daratumumab

Ibrutinib

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunologic Factors

Tyrosine Kinase Inhibitors

Tyrosine

Prephase (D-27 to D0): ibrutinib 420 mg/day

Cycle 1 (4 weeks): ibrutinib 420 mg/day from D1 to D28 + daratumumab 8 mg/kg D1 and D2, then 16 mg/kg at D8, D15, D22.

Cycle 2 (4 weeks): ibrutinib 420 mg/day D1 to D28 + daratumumab 16 mg/kg at D1, D8, D15 and D22.

Cycles 3 to 6 (4 weeks) : ibrutinib 420 mg/day D1 to D28 + daratumumab 16 mg/kg at D1 and D15.

Cycles ≥ 7 (4 weeks) : ibrutinib 420 mg/day D1 to D28 + daratumumab 16 mg/kg at D1.

Ibrutinib will be given at the fixed dose of 420 mg daily for the duration of treatment.

Daratumumab will be started 28 days after beginning of ibrutinib and will be administered at the standard dose of 16 mg/kg (divided over two days for the first infusion), then 16 mg/kg for the following infusions, weekly for 2 months, then every other week for 4 months and then once a month until progression or intolerance.

Alain DELMER, MD PD

Thérèse AURRAN-SCHEINLITZ, MD

Ibrutinib, a first-in-class Bruton Tyrosine kinase (BTK) inhibitor, has become an established treatment in relapsed/refractory chronic lymphocytic leukemia (CLL). However, despite a considerable improvement of Progression Free Survival (PFS) and Overall Survival (OS) in comparison with historical controls, the prognosis of patients with 17p deletion (del17p) remains a concern, as it is clearly much less favourable than that of patient without del17p. Again, TP53 mutations correlated to poorer prognostic in Relapsed/Refractory (R/R) CLL patients treated with ibrutinib (Brown JR et al,2018). Despite these therapeutic advances, the treatment of CLL with TP53 disruption thus remains a difficult issue that warrants evaluation of alternative treatment strategies, in particular the use of ibrutinib in combination with other agents. A body of evidence suggests that targeting the extracellular molecule CD38 might be an interesting option. CD38 is a transmembrane glycoprotein with multiple receptor and enzymatic functions. The interaction of CD38 with its ligand CD31 (also known as Platelet Endothelial Cell Adhesion Molecule (PECAM-1)) not only plays a role in the binding and the migration of leucocytes through the endothelial cells wall but also triggers the activation of intracellular pathways involved in the differentiation and activation of B cells. Previous results strongly suggest that CD38 favours the expansion of CLL clones not only directly by transducing a proliferation signal but also by directing them to anatomic sites where they find favourable conditions for proliferation and survival.

Daratumumab is a first-in-class human IgG1ĸ monoclonal antibody (mAb) that binds CD38-expressing malignant cells with high affinity. Daratumumab induces tumor cell death through multiple mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP) and induction of apoptosis (de Weers et al, 2011). Recent data show that daratumumab may also display an immunomodulatory effect through depletion of a subset of immunosuppressive CD38+ Tregs (Krejcik et al, 2016). Early-stage clinical trials found daratumumab to be safe and to display encouraging clinical activity as a single agent in relapsed/refractory multiple myeloma (MM) patients (Lockhorst et al 2016, Lonial et al, 2016). Overall response rate was 31%, with rapid (median 1 month) and durable responses in this heavily pretreated MM population. Interestingly, no patient discontinued the treatment because of drug-related adverse events. These results led to approval of daratumumab in relapsed/refractory MM in December 2015. The clinical efficacy of daratumumab along with its very favourable safety profile supports its investigation in other lymphoproliferative malignancies. In particular, the expression of CD38 in poor prognosis CLL and the key role of CD38 in CLL biology provide a basis for examining the potential of daratumumab in this disease.

In preclinical studies, (Matas-Céspedes et al, 2016; Manna et al, 2017) Daratumumab efficiently kills CLL cell lines and patient-derived CLL cells by ADCC and ADCP in vitro. Daratumumab modulates CLL-T reg levels and increase cytotoxic effector T cells.

Rationale for combining ibrutinib with daratumumab:

These data suggest that combining ibrutinib with daratumumab might have a synergistic or additive effect. Both drugs inhibit B cell receptor (BCR) signalling via two different converging pathways, i.e. BTK and CD38/ZAP70/ERK (Deaglio et al, 2007). In vitro, Manna et al have shown that daratumumab is able to modulate BCR signaling.

Interestingly, the ibrutinib /daratumumab combination significantly enhanced mitochondrial-mediated apoptosis bth in CD38 high and CD38 low CLL cells (Manna et al, 2017).

Altogether, this provides a rationale for evaluating the safety and efficacy of the association of daratumumab with ibrutinib in high-risk relapsed/refractory patients for whom the standard-of-care using ibrutinib as a single agent has demonstrated limitations in terms of long-term disease control.

Primary objective of the study: to determine the efficacy of a treatment combining daratumumab and ibrutinib in a poor risk population of relapsed CLL patients with TP53 dysfunction.

Secondary objectives of the study : to determine the safety profile of daratumumab in combination with ibrutinib in CLL patients.

Inclusion period: 24 months Treatment duration (ibrutinib + daratumumab): continuous, until disease progression or unacceptable toxicity.

Follow-up period: will begin once the subject discontinues study treatment, during 2 years.

This study will take place in several periods and phases of treatment:

* Observational period of selection of 28 days maximum
* Treatment period constituted:

  * a first phase of treatment with ibrutinib alone (28 days): pre-phase,
  * a formal protocol phase during which the two study drugs (ibrutinib and daratumumab) will be used together until progression of the disease or intolerance to treatment.
* 2-year follow-up period that will begin after protocol processing has been stopped.

Selection period (before starting treatment): exams performing to verify patients' eligibility.

* Collection of the medical history,
* Clinical examination with measurement of height and weight, vital signs (temperature, pulse / heart rate, blood pressure),
* Conventional blood tests to check all the functions of the body such as kidney, liver, etc
* Viral serologies (Human Immunodeficiency Virus (HIV) and hepatitis B and C) (10 ml).
* Blood Pregnancy Test for women who may have children,
* Specific blood tests to evaluate the disease and in particular to characterize the cells of LLC (mutational profile, search for chromosomal abnormalities and analysis of residual disease rate to have a reference point before the start of treatment will be made on leukemic cells),
* CT scan (thorax, abdomen and pelvis) to accurately search for and evaluate a deep tumor syndrome (lymph nodes, spleen in particular),
* Urine examination,
* Cardiological examination with an electrocardiogram (ECG)..

Treatment period: the treatment period is divided into successive cycles of 28 days.

Before starting ibrutinib and before each daratumumab cycle, a complete clinical examination and blood work will be performed.

After 12 months of treatment, an evaluation report will be made with a complete clinical examination, a complete blood test, an urinalysis if necessary, a Computed Tomography (CT) scan, a myelogram and if necessary a marrow biopsy. Regularly after this assessment (every 6 months until the end of the study), a report will be made with clinical examination, complete blood test, ECG, CT scan and if necessary, myelogram possibly associated with a marrow biopsy if justified and not previously carried out.

After the end of the protocol treatment (progression of the disease, intolerance of the protocol treatment), a last evaluation will be carried out within 30 days after the last taking of the protocol treatment. This evaluation includes a complete clinical examination, biological tests (complete blood test) and a CT scan.

Follow-up period the completed treatment you will then be followed in consultation every 6 months for 2 years to evaluate the duration of the response to treatment and thus meet the objectives of the study.

Evaluation of the Safety and Efficacy of the Association of Ibrutinib and Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia With p53 Dysfunction

A Phase II Pilot Study to Evaluate the Safety and Efficacy of the Association of Ibrutinib and Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia With p53 Dysfunction. IDA53 Trial

Deep phenotyping by high dimensional single cell mass cytometry (CyTOF) of peripheral blood cells

Treatment response (ratio between the number of patients achieving complete response and the total number of patients included

Frequency and severity of tumor lysis syndrome

Incidence and severity of study treatment-Emergent Adverse Events utilizing National Cancer Institute - Common Terminology Criteria (NCI-CTC) criteria v4.03.

Overall response (OR) rate, partial response (PR) rate, PR with lymphocytosis rate

Presence of MRD measured by either quantitative PCR or flow cytometry

time interval between the date of inclusion in the trial the date of progression of the illness or death

time interval between the date of inclusion in the trial and the date of death

time elapsed between the date of obtaining a maximal objective response (CR, PR or PR with persistent lymphocytosis) and the date of progression of the disease or death

CD38 expression rate by immunophenotyping

Number of patients who develop a Richter's syndrome

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer	NCT02203513	Ovarian Cancer Breast Cancer Prostate Cancer	LY2606368	18 Years -	National Institutes of Health Clinical Center (CC)
A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer	NCT02203513	Ovarian Cancer Breast Cancer Prostate Cancer	LY2606368	18 Years -	National Institutes of Health Clinical Center (CC)
Evaluation of the Safety and Efficacy of the Association of Ibrutinib and Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia With p53 Dysfunction	NCT03734198	Relapsed or Ref...	Ibrutinib Daratumumab	18 Years -	French Innovative Leukemia Organisation
Evaluation of the Safety and Efficacy of the Association of Ibrutinib and Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia With p53 Dysfunction	NCT03734198	Relapsed or Ref...	Ibrutinib Daratumumab	18 Years -	French Innovative Leukemia Organisation

Spots Global Cancer Trial Database for p53 dysfunction