Testing the Use of Nilotinib and Paclitaxel as a Treatment for Patients With Prior Taxane Treatment, A ComboMATCH Treatment Trial

Study Overview
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Brief Summary
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This phase II ComboMATCH treatment trial evaluates nilotinib with paclitaxel for the treatment of patients with solid cancers that are growing, spreading, or getting worse (progressive) and that have previously been treated with taxane therapies. Nilotinib is in a class of medications called kinase inhibitors. It works by binding to and blocking the action of a protein called ABL, which signals tumor cells to multiply. This helps slow or stop the proliferation of tumor cells. Paclitaxel is a drug that blocks cell growth by stopping cell division and it may kill tumor cells. Giving nilotinib with paclitaxel may be effective at treating patients with progressive solid cancers that have previously been treated with taxane therapies.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the proportion of patients with taxane-refractory advanced malignancies who have objective responses (OR) to treatment with nilotinib hydrochloride monohydrate (nilotinib) and paclitaxel. SECONDARY OBJECTIVE: I. Collect tissue and provide it to the ComboMATCH registration protocol to assess concordance between the diagnostic tumor mutation profile generated by the designated laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) mutation profile from plasma, as described in ComboMATCH registration protocol. For this treatment substudy, the outcome objective will be to report the proportion of cases providing sufficient tissue for that integrated scientific activity in the ComboMATCH registration protocol. EXPLORATORY OBJECTIVES: I. To evaluate progression free survival (PFS) at 6 months on study agents. II. To identify genomic and transcriptomic determinants of response and resistance in tumor biopsy specimens and cell-free deoxyribonucleic acid (DNA). OUTLINE: Patients receive nilotinib hydrochloride monohydrate orally (PO) twice daily (BID) on days 1-28 and paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study. Patients also undergo collection of blood samples and tumor biopsy on study. After completion of study treatment, patients are followed until disease progression, and for survival for 3 years from registration.

Official Title
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Nilotinib and Paclitaxel in Patients With Prior Taxane-Treated Solid Tumors: A ComboMATCH Treatment Trial

Conditions
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Metastatic Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Drug: Nilotinib Hydrochloride Monohydrate
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be enrolled on the ComboMATCH registration protocol (EAY191) at the time of registration to the EAY191-E4 study Patient must be >= 18 years of age Patient must not have any of the following mutations (as determined by the ComboMATCH registration protocol), which are known to confer sensitivity or resistance to nilotinib monotherapy: KIT: W557R, V559D, V559A, L576P, and K642E PDGFR-alpha: D842V Patient must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH registration trial (EAY191) NOTE: The current actionable mutation of interest (aMOI)/actionable alteration list for this treatment trial can be found on the Cancer Trials Support Unit (CTSU) website NOTE: Novel/dynamic aMOI can be submitted for review per the process described in the ComboMATCH registration protocol Patient must be willing to provide blood samples for research purposes Patient must have had at least one prior line of therapy in the metastatic setting Patient must have previously undergone taxane therapy (in the metastatic setting) Patients who previously responded to prior taxane therapy must have received their last dose of taxane therapy within 6 months prior to EAY191-E4 registration and have had no other intervening treatment prior to EAY191-E4 registration Patients who did not respond to prior taxane therapy are eligible regardless of the time elapsed since the prior taxane therapy or any other intervening therapies Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Patient must not have had platinum-resistant epithelial serous ovarian cancer Patient must not have peripheral neuropathy > grade 1 Patients must not have neuropathy >= grade 2 within 14 days of registration/randomization Patient must have documented QT interval with Fridericia's correction (QTcF) of =< 450 msec within 8 days prior to EAY191-E4 registration. Patients with a QTcF interval of >= 450 msec at registration or patients with congenital long QT syndrome are not eligible Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for at least 3 months after the last dose of study drug Patients must have progressive disease Absolute neutrophil count (ANC) >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (with the exception of those with Gilbert syndrome, who must have total bilirubin =< 3 x institutional ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 institutional upper limit of normal; < 5.0 x ULN in patients with liver metastases Creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 mg/dL Patient must have the ability to swallow medications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nilotinib hydrochloride monohydrate, paclitaxel)<br>Patients receive nilotinib hydrochloride monohydrate PO BID on days 1-28 and paclitaxel IV over 1 hour on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI throughout the study. Patients also undergo collection of blood samples and tumor biopsy on study. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Nilotinib Hydrochloride Monohydrate<br>* Given PO<br>* Other names: Tasigna;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best objective response | Evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. 90% two-sided confidence intervals will be used for reporting estimated rates. | Up to 3 years | 
| Progression free survival | Distribution will be estimated using the method of Kaplan and Meier. | From registration to documented disease progression or death from any cause, assessed up to 3 years | 
| Overall survival | Distribution will be estimated using the method of Kaplan and Meier. | From registration to death from any cause, assessed up to 3 years | 
| Incidence of adverse events | Will be determined using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Exact binomial confidence intervals will be used for adverse event rates. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concordance of diagnostic tumor mutation profile, pre-treatment tumor biopsy mutation profile, and pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) profile | Whole-exome sequencing, ribonucleic acid sequencing, and ctDNA sequencing will be performed on mandatory tissue biopsies and/or blood specimens. | Up to 3 years |