Ceritinib and Combination Chemotherapy in Treating Patients With Advanced Solid Tumors or Locally Advanced or Metastatic Pancreatic Cancer

NCT02227940 | Completed Phase 1 DMC

• 2 other identifiers: I 248813NCI-2014-01766
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of ceritinib and combination chemotherapy in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or has spread to other places in the body (metastatic). Ceritinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ceritinib and more than one drug (combination chemotherapy) may be a better treatment for solid tumors or pancreatic cancer.

Conditions

Advanced Malignant Solid Neoplasm; ALK Positive; Metastatic Pancreatic Adenocarcinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

Outcome Measures

Primary Outcomes (3)

• MTD and RP2D of ceritinib in combination with gemcitabine hydrochloride alone, defined as the highest dose level at which < 2 of 6 patients experience treatment-related dose limiting toxicity (DLT) (Arms 1 and 1E)

  Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.0. The frequency of toxicities will be tabulated for the dose estimated to be the MTD.

  Up to day 28

• MTD and RP2D of ceritinib in combination with gemcitabine hydrochloride and cisplatin, defined as the highest dose level at which < 2 of 6 patients experience treatment-related DLT (Arms 3 and 3E)

  Graded according to NCI CTCAE v4.0. The frequency of toxicities will be tabulated for the dose estimated to be the MTD.

  Up to day 28

• MTD and RP2D of ceritinib in combination with gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation, defined as the highest dose level at which < 2 of 6 patients experience treatment-related DLT (Arms 2 and 2E)

  Graded according to NCI CTCAE v4.0. The frequency of toxicities will be tabulated for the dose estimated to be the MTD.

  Up to day 28

Secondary Outcomes (6)

• Incidence of adverse events of ceritinib in combination with gemcitabine hydrochloride based chemotherapy in advanced solid malignancies according to NCI CTCAE v4.0

  Up to 4 weeks after end of treatment

• Pharmacokinetic parameters of ceritinib and gemcitabine hydrochloride when administered in combination in patients with advanced solid tumors (Arms 1 and 1E)

  Pre-dose, 0.5, 1-2, 4-5, 6-8, and 24 hours (day 1 of courses 1-2), pre-dose on day 15 of course 1 (ceritinib); prior to end of infusion, 0.5, 1-2, and 4-6 hours post-end of infusion (day 1 of courses 1-2) (gemcitabine hydrochloride)

• Pharmacokinetic parameters of ceritinib, gemcitabine hydrochloride, and paclitaxel albumin-stabilized nanoparticle formulation when administered in combination in patients with advanced solid tumors (Arms 2 and 2E)

  Pre-dose, 0.5, 1-2, 4-5, 6-8, and 24 hours (day 1 of courses 1-2), pre-dose on day 15 of course 1 (ceritinib); prior to end of infusion, 0.5, 1-2, and 4-6 hours post-end of infusion (day 1 of courses 1-2) (gemcitabine hydrochloride and nab-paclitaxel)

• Pharmacokinetic parameters of paclitaxel albumin-stabilized nanoparticle formulation, and cisplatin when administered in combination in patients with advanced solid tumors (Arms 3 and 3E)

  Pre-dose, 0.5, 1-2, 4-5, 6-8, and 24 hours (day 1 of courses 1-2), pre-dose on day 15 of course 1 (ceritinib); prior to end of infusion, 0.5, 1-2, and 4-6 hours post-end of infusion (day 1 of courses 1-2) (gemcitabine hydrochloride and cisplatin)

• Progression free survival

  Up to 4 weeks after end of treatment

Other Outcomes (1)

• Levels of serum and tumor biomarkers

  Up to 4 weeks after end of treatment

Study Arms (3)

Arm 1 (ceritinib MTD then with gemcitabine alone)

EXPERIMENTAL

Dose Escalation Cohort 1: Patients with advanced solid tumors for whom gemcitabine hydrochloride-based therapy is clinically appropriate receive ceritinib PO (QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Expansion Cohort 1E: Once the MTD of ceritinib has been determined, an additional 10 patients with ALK-positive advanced solid tumors who previously progressed on gemcitabine hydrochloride-based therapy receive ceritinib and gemcitabine hydrochloride as in the dose escalation cohort 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Ceritinib; Drug: Gemcitabine Hydrochloride; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel)

EXPERIMENTAL

Dose Escalation Cohort 2: Patients with advanced pancreatic cancer receive ceritinib PO QD on days 1-28, gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15, and paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Expansion Cohort 2E: Once the MTD of ceritinib has been determined, patients with ALK-positive advanced solid tumors receive ceritinib, gemcitabine hydrochloride, and paclitaxel albumin-stabilized nanoparticle formulation as in the dose escalation cohort 2. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Ceritinib; Drug: Gemcitabine Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation; Other: Pharmacological Study

Arm 3 (ceritinib MTD then with gemcitabine and cisplatin)

EXPERIMENTAL

Dose Escalation Cohort 3: Patients with advanced solid tumors for whom gemcitabine hydrochloride and cisplatin-based therapy is clinically appropriate receive ceritinib PO QD on days 1-28, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and cisplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Expansion Cohort 3E: Once the MTD of ceritinib has been determined, an additional 10 patients with ALK-positive advanced solid tumors receive ceritinib, gemcitabine hydrochloride, and cisplatin as in the dose escalation cohort 3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Ceritinib; Drug: Cisplatin; Drug: Gemcitabine Hydrochloride; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

Interventions

Ceritinib DRUG

Given PO

Also known as: LDK 378, LDK378, Zykadia

Arm 1 (ceritinib MTD then with gemcitabine alone); Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel); Arm 3 (ceritinib MTD then with gemcitabine and cisplatin)

Cisplatin DRUG

Given IV

Also known as: Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin

Arm 3 (ceritinib MTD then with gemcitabine and cisplatin)

Gemcitabine Hydrochloride DRUG

Given IV

Also known as: dFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011

Arm 1 (ceritinib MTD then with gemcitabine alone); Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel); Arm 3 (ceritinib MTD then with gemcitabine and cisplatin)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm 1 (ceritinib MTD then with gemcitabine alone); Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel); Arm 3 (ceritinib MTD then with gemcitabine and cisplatin)

Paclitaxel Albumin-Stabilized Nanoparticle Formulation DRUG

Given IV

Also known as: ABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, nab-paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, protein-bound paclitaxel

Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel)

Pharmacological Study OTHER

Correlative studies

Arm 1 (ceritinib MTD then with gemcitabine alone); Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel); Arm 3 (ceritinib MTD then with gemcitabine and cisplatin)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Arm 1: histologically or cytologically confirmed solid tumors that are advanced that gemcitabine-based treatment is considered a clinically appropriate option
• Arm 2: histologically or cytologically confirmed adenocarcinoma of the pancreas that is locally advanced or metastatic
• Arm 3: histologically or cytologically confirmed solid tumors that are advanced that gemcitabine plus cisplatin treatment is considered a clinically appropriate option
• Arms 1E, 2E and 3E: solid tumor that demonstrate anaplastic lymphoma kinase (ALK) positivity; ALK positivity can be assessed using the assays below, and documentation of ALK positivity using one of the tests below is required
• Fluorescence in situ hybridization (FISH) test for ALK positivity using the Food and Drug Administration (FDA)-approved FISH test (Abbott Molecular Inc), using Vysis breakapart probes (defined as 15% or more positive tumor cells); OR
• Harboring a confirmed ALK positivity, as determined by positivity to the Ventana immunohistochemistry (IHC) assay
• Arms 1E: previously treated with and progressed on gemcitabine-containing therapy
• Arms 1, 2, 3: patients should have clinically measurable or evaluable malignant disease
• Arms 1E, 2E, 3E: patients with at least one measurable site of disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 that have not been previously irradiated
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1
• Life expectancy \>= 3 months
• Absolute neutrophil count (ANC) \>= 1,500 cells/mm\^3 (system international \[SI\] units 1.5 x 10\^9/L)
• Platelets \>= 100,000 cells/mm\^3 (SI units 100 x 10\^9/L)
• Hemoglobin \>= 9 g/dL (SI units 90 g/L) (in the absence of transfusion within 24 hours prior to dosing)
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =\< 3 x upper limit of normal (ULN); in patients with known hepatic involvement, AST and ALT =\< 5 x ULN are allowed

You may not qualify if:

• Arms 2, 2E, 3, 3E: patients who previously received \> 2 lines of systemic chemotherapy for advanced or metastatic disease
• Previous pelvic radiation affecting \>= 25% of the bone marrow; patients who received whole pelvic radiation are excluded
• Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding nitrosourea, mitomycin-C, targeted therapy and radiation) =\< 4 weeks prior to starting study drug
• Patients who have received the last administration of nitrosourea or mitomycin-C =\< 6 weeks prior to starting study drug
• Patients who have had radiotherapy =\< 4 weeks prior to starting study drug, or =\< 2 weeks prior to starting study drug in the case of localized radiotherapy (e.g., for analgesic purpose or for lytic lesions at risk of fracture)
• Patients who have received targeted therapy (e.g., sunitinib, sorafenib, pazopanib), except ALK inhibitors, =\< 2 weeks prior to starting study drug
• Patients who have residual toxicity(-ities) from previous anti-cancer treatment(s) that is/are clinically significant or \> grade 1 are excluded; those whose toxicity(-ities) improved to grade 1 or better will be eligible
• The patient is less than 5 half-lives from prior ALK inhibitor or targeted therapy (for adequate wash-out) without recovery from treatment toxicities to \< grade 1 or to their pre-treatment levels
• Patients with known history of extensive disseminated bilateral interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention)
• Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury =\< 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device =\< 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
• Known hypersensitivity or infusion reaction to cisplatin and gemcitabine
• Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
• Receiving medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with ceritinib and for the duration of participation:
• Medication with a known risk of prolonging the QT interval or inducing torsades de pointes
• Strong inhibitors or strong inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/5

Sponsors & Collaborators

• Roswell Park Cancer Institute: lead
• Novartis: collaborator

Study Sites (1)

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

ceritinib; Cisplatin; 1,2-diaminocyclohexaneplatinum II citrate; Platinum; Gemcitabine; Taxes; Albumin-Bound Paclitaxel; 130-nm albumin-bound paclitaxel

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Metals, Heavy; Elements; Transition Elements; Metals; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Economics; Health Care Economics and Organizations; Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Renuka Iyer

  Roswell Park Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2014
• First Posted: August 28, 2014
• Study Start: January 8, 2015
• Primary Completion: December 27, 2018
• Study Completion: February 12, 2019
• Last Updated: July 25, 2022

Record last verified: 2022-07

Locations

US (1)