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Cholangiocarcinoma

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All Drugs and Chemicals

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Patients receive olaparib PO BID on days 1-28 of each cycle and ceralasertib PO QD on days 1-7 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsies during screening and on study, collection of blood samples throughout the trial, and undergo CT and/or MRI scans throughout the trial. Patients may also undergo bone marrow aspiration and biopsy as clinically indicated on study.

Biopsy

Biospecimen Collection

Undergo bone marrow aspiration and biopsy

Bone Marrow Aspiration

Bone Marrow Biopsy

Ceralasertib

Computed Tomography

Magnetic Resonance Imaging

Patricia M LoRusso

This phase II trial studies how well olaparib and ceralasertib (AZD6738) work in treating patients with IDH mutant cholangiocarcinoma or solid tumors. Cancer is caused by changes (mutations) to genes that control the way cells function. Laboratory studies have shown that olaparib and AZD6738 can shrink IDH mutant tumors or stop them from growing. Olaparib and ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the overall response rates of olaparib and ceralasertib (AZD6738) in subjects with recurrent/progressive IDH1/2-mutant solid malignant tumors, who will be recruited to 2 cohorts:

Ia. Cholangiocarcinoma (cohort has been closed to accrual); Ib. Other solid malignant tumors.

SECONDARY OBJECTIVES:

I. To assess the progression free survival (PFS) of olaparib and AZD6738 in adults with recurrent/progressive IDH1/2-mutant solid malignant tumors.

II. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- mutant solid malignant tumors.

III. To assess the duration of response in adults with recurrent/progressive IDH1/2-mutant solid malignant tumors.

IV. To assess the safety and tolerability of the combination of olaparib and AZD6738.

EXPLORATORY OBJECTIVES:

I. To evaluate 2-hydroxyglutarate (2HG) concentration in plasma by mass spectrometry and correlate with treatment response.

II. To evaluate 2HG levels in tumor biopsies prior to the beginning of treatment and while on therapy and correlate with treatment response.

III. Correlate 2HG concentration in plasma and in tumor biopsies. IV. To evaluate deoxyribonucleic acid (DNA) double strand breaks (DSBs) as measured by mass cytometry time of flight (CyTOF)-imaging mass cytometry (IMC) in tumor biopsies before and after treatment with olaparib and AZD6738.

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 of each cycle and ceralasertib PO once daily (QD) on days 1-7 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsies during screening and on study, collection of blood samples throughout the trial, and undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) scans throughout the trial. Patients may also undergo bone marrow aspiration and biopsy as clinically indicated on study.

After completion of study treatment, patients are followed up for 30 days.

Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors

A Phase II Study of Olaparib and AZD6738 in Isocitrate Dehydrogenase (IDH) Mutant Solid Tumors

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Absolute and fold changes for gamma H2AX foci will be calculated between baseline and subsequent follow-up (pre-treatment and on-treatment biopsies). These will be displayed graphically versus (vs). time for each cohort. Differences will be plotted vs. response status. Wilcoxon sign-rank test as well as paired t-tests will be used to evaluate if differences between baseline and each subsequent time point are significant. Summary statistics will be reported (with 95% confidence intervals) to demonstrate mean differences in fold-change (or log fold-change) between responders and non-responders.

2HG levels in tumor and plasma will be compared to treatment responses. The Mann-Whitney U test will be used to test for differences in post-treatment tissue and plasma 2HG concentrations between patients with a response to treatment and those without. Will also apply analysis of covariance for post-treatment plasma concentration in 2HG adjusted for the pre-treatment plasma concentration between patients with a response to treatment and those without.

The exact two-sided 95% confidence intervals (CIs) for the ORR will be reported.

PFS will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on the Greenwoods variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the odds ratios and the adjusted 95% confidence interval will be reported.

OS will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on the Greenwoods variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the odds ratios and the adjusted 95% confidence interval will be reported.

Will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on the Greenwoods variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the odds ratios and the adjusted 95% confidence interval will be reported.

Toxicities will be evaluated utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

National Cancer Institute (NCI)

Klatskin Tumor

Intrahepatic Cholangiocarcinoma

Hematinics

Liver Extracts

Patients receive NXP800 PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, and/or PET at baseline and on study. Patients may optionally undergo ultrasound-guided liver biopsy and/or collection of blood samples on study and during follow up.

Heat Shock Factor 1 Pathway Inhibitor NXP800

Positron Emission Tomography

Ultrasound-Guided Biopsy

Clinical Trials Referral Office

Mitesh J. Borad, M.D.

This phase I trial tests the safety, best dose, and effectiveness of NXP800 in treating patients with cholangiocarcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). NXP800 inhibits a pathway called the heat shock factor 1 (HSF1) pathway. The inhibition of this pathway inhibits proliferation, migration, survival, and metastasis in susceptible tumor cells. Overexpressed, amplified and/or overactivated in many cancer cells, HSF1 activates a set of genes that play a key role in tumor initiation, progression and metastasis. Inhibiting this pathway may in turn inhibit tumor initiation, progression, and/or metastasis. Giving NXP800 may be safe, tolerable and/or effective in treating patients with advanced or metastatic cholangiocarcinoma.

PRIMARY OBJECTIVE:

I. To determine the maximum tolerated dose (MTD)/recommended phase 2 dose for heat shock factor 1 pathway inhibitor NXP800 (NXP800).

SECONDARY OBJECTIVES:

I. To determine the toxicity profile of NXP800. II. To determine the best response for NXP800 using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

III. To estimate the overall survival (OS) for NXP800. IV. To estimate the progression-free survival (PFS) for NXP800.

EXPLORATORY OBJECTIVES:

I. To evaluate transcriptomic features associated with sensitivity, resistance and pharmacodynamic effect of NXP800 using serial ribonucleic acid-sequencing (RNA-Seq).

II. To assess tumor evolution with NXP800 using serial whole genome-sequencing (Seq).

III. To assess tumor evolution with NXP800 using serial circulating tumor deoxyribonucleic acid (DNA) (ct-DNA).

IV. To estimate tumor marker response using serial CA19-9/carcinoembryonic antigen (CEA).

OUTLINE: This is a dose de-escalation study of NXP800 followed by a dose-expansion study.

Patients receive NXP800 orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET) at baseline and on study. Patients may optionally undergo ultrasound-guided liver biopsy and/or collection of blood samples on study and during follow up.

After completion of study treatment, patients are followed up every 6 months until progressive disease or death for up to 3 years.

NXP800 for the Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma

Phase 1b Study of the Novel GCN2 Kinase Activator NXP800 in Patients With Advanced Cholangiocarcionoma

MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients.

Recommended phase 2 dose is based on MTD (Outcome 1).

Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. The grade 3+ adverse events will also be described and summarized in a similar fashion.

Best response is defined to be the best objective status recorded. The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. The Response Evaluation Criteria in Solid Tumors 1.1 criteria will be used for tumor evaluation and patients will be re-evaluated every 8 weeks. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by dose level). The number of responses may indicate further evaluation for specific tumor types in a phase II setting.

OS will be estimated using the Kaplan-Meier method. The median OS and corresponding 95% confidence interval (by Brookmeyer and Crowley) will be reported.

PFS will be estimated using the Kaplan-Meier method. The median PFS and corresponding 95% confidence interval (by Brookmeyer and Crowley) will be reported.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors	NCT03878095	Malignant Solid... Refractory Chol... Refractory Mali...	Biopsy Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Ceralasertib Computed Tomogr... Magnetic Resona... Olaparib	18 Years -	National Cancer Institute (NCI)
NXP800 for the Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma	NCT06420349	Advanced Cholan... Metastatic Chol... Refractory Chol... Stage III Hilar... Stage III Intra... Stage IV Hilar ... Stage IV Intrah...	Biospecimen Col... Computed Tomogr... Heat Shock Fact... Magnetic Resona... Positron Emissi... Ultrasound-Guid...	18 Years -	Mayo Clinic
Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors	NCT03878095	Malignant Solid... Refractory Chol... Refractory Mali...	Biopsy Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Ceralasertib Computed Tomogr... Magnetic Resona... Olaparib	18 Years -	National Cancer Institute (NCI)
NXP800 for the Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma	NCT06420349	Advanced Cholan... Metastatic Chol... Refractory Chol... Stage III Hilar... Stage III Intra... Stage IV Hilar ... Stage IV Intrah...	Biospecimen Col... Computed Tomogr... Heat Shock Fact... Magnetic Resona... Positron Emissi... Ultrasound-Guid...	18 Years -	Mayo Clinic

Spots Global Cancer Trial Database for refractory cholangiocarcinoma