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Gemcitabine

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To determine the recommended phase 2 dose (RP2D) for gemcitabine Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib in patients with untreated metastatic PDAC.

To determine the efficacy of the RP2D identified in Part A in untreated metastatic PDAC patients

The RP2D of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel determined in Part A will be used in Part B dose expansion.

avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel

Verastem Call Center

Dalila Stanfield

Andrew Ko, MD

Clinical Trials

Shergill Ardaman, MD

Kimberly Perez

Kimberly Perez, MD

Lynne Mitchell

Kian-Huat Lim, MD

Kristen Spencer

Kristen Spencer, DO

Casey Owens

Despina Siolas, MD

Anna Varghese, MD

Luda Mazaleuskya

Mark O'Hara, MD

Sierra Mitchell

Ignacio Garrido-Laguna

Colleen Soleau

Vincent Picozzi, MD

Rachael Safyan

Rachael Safyan, MD

MD Verastem

This study will assess the safety and efficacy of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel in patients with Pancreatic Ductal Adenocarcinoma (PDAC) who have been previously untreated.

This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety, tolerability and efficacy of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel in patients previously untreated metastatic Pancreatic Ductal Adenocarcinoma (PDAC).

Study of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer

A Phase 1b/2a Study of Gemcitabine and Nab-paclitaxel in Combination With Avutometinib (VS-6766) and Defactinib in Patients With Previously Untreated Metastatic Adenocarcinoma of the Pancreas

Assessment of Dose-limiting toxicities (DLTs)

Confirmed overall response rate (ORR) (partial response \[PR\] + complete response \[CR\] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST 1.1\])

Time of first response to PD as assessed per RECIST 1.1

From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause

Area under plasma Concentration (AUC) 0 to t

Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale

Count of abnormal laboratory values by grade

Verastem, Inc.

Carcinoma

Carcinoma, Neuroendocrine

Exocrine Pancreatic Insufficiency

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

A prospective cross-sectional assessment of the prevalence of PEI-related symptoms in up to n=150 patients with pancreatic malignancy.

A sub-set (up to n=50) of the Demographic cohort patients will be tested to elucidate the most efficient diagnostic panel for PEI in pancreatic malignancy.

An extra assessment for PEI diagnosis consisting of a breath test (Pancreo-KIT breath test) will be carried out during the following 1-2 weeks after the first appointment (which takes around six hours to complete and involves the administration of bread spread with 13C butter followed by collection of the patient's breath in small plastic vials at timed intervals. The vials will subsequently be analyzed for 13C quantity; details in Appendix 6). Following these diagnostic tests, patients will complete an "acceptability questionnaire" to assess their opinion regarding the burden that these diagnostic tests may add.

Validation of the diagnostic panel designed and tested in Step-1 of this study and evaluation of dietician intervention (including Pancreatic Enzyme Replacement Therapy; PERT) and its impact in weight loss, symptom evolution, chemotherapy receiving rate, quality of life and overall survival.

Pancreo-Kit (Isomed Pharma, Madrid, Spain) is a breath test devised to measure Pancreatic Enzyme Insufficiency. It is a non-invasive method to obtain information about the digestion of consumed lipids; this in turn is informative about the exocrine enzyme activity of the pancreas (specifically pancreatic lipase). This kit is manufactured to EC directive 98/79/EEC and carries the CE mark.

The test is based on measurement of 13C which is a stable naturally occurring environmental isotope of carbon with a nucleus containing 6 protons and 7 neutrons (note, it is not radioactive).

Pancreo-KIT breath test

Juan W Valle, Professor

This is a prospective observational study which aims to evaluate;

The prevalence of pancreatic insufficiency in patients with pancreatic malignancies (adenocarcinoma and neuroendocrine tumours).

The most appropriate diagnostic strategy. The impact that an adequate diagnosis and treatment may have on patients' outcome.

Patients will prospectively receive a full nutritional assessment, pancreatic enzyme insufficiency (PEI) diagnosis and dietician education. This assessment will be performed as an outpatient in parallel with the medical oncology team, by the research dietician. This study will be performed in two steps (summarized in Figure 2);

Step-1 \| A prospective cross-sectional assessment of the prevalence of PEI-related symptoms in up to n=150 patients with pancreatic malignancy (this will be termed 'the demographic cohort'). A sub-set of these patients (n=50) will be tested to elucidate the most efficient diagnostic panel for PEI in pancreatic malignancy (this will be termed 'the diagnosis cohort').

Step-2 \| A prospective longitudinal validation of the diagnostic panel designed and tested in Step-1 and evaluation of dietician intervention (including PERT) and its impact in weight loss, symptom evolution, chemotherapy receiving rate, Quality of Life and overall survival (this will be termed 'the follow-up cohort' and will include up to n=50 patients).

All patients included in both steps will have a full nutritional assessment at baseline, and PERT treatment (as per standard of care if considered appropriate). Patients in the follow-up cohort will be reviewed (at least every 3 months for a maximum of 6 months since study entry) by dietician for further intervention and assessment.

Pancreatic Cancer Dietary Assessment Study

Prospective Observational Study of Prevalence, Assessment and Treatment of Pancreatic Insufficiency in Patients With Pancreatic Malignancies

Prevalence will be given as a percentage of all patients with pancreatic neoplasms with evidence of pancreatic enzyme insufficiency

Percentage of patients with documented biochemical evidence of pancreatic enzyme insufficiency with related symptoms

Described as a percentage of successful tests completed by patients

To quantify acceptability on a pre-defined score for each of the tests.

Themes will be described in a semi-quantitative report arising from the interviews.

Pancreatic Cancer UK

The Christie NHS Foundation Trust

The 22-gauge core biopsy needle with reverse bevel design (EchoTip® Procore™) will be compared prospectively to the standard straight hollow-core 22-gauge or 25-gauge FNA needle already used in our clinical practice for the diagnosis of solid pancreatic lesions.

Two passes performed with the standard 22-gauge or 25-gauge straight hollow core needle and two passes will be performed using the 22-gauge EchoTip® Procore™ needle. All passes will be taken from a single lesion and from the same endoscopic location.

Novel 22-gauge Core Biopsy Needle + Standard Biopsy Needle

Brian Weston, MD

The goal of this clinical research study is to compare the performance of a newly available needle with reverse bevel design (called the EchoTip® Procore™ needle) with standard needles to see which needle gives better diagnostic information for pancreatic lesions.

An endoscopic ultrasound-guided needle biopsy or FNA is a special endoscopic procedure used to sample lesions within or next to the digestive tract, including the pancreas. The needle is used to collect material for diagnosis. A special lighted, flexible tube called an endoscope is inserted through the mouth, into the stomach and small intestine. The endoscope also has an ultrasound probe at its tip which can be used to see the pancreas, which is located behind the stomach. The doctor will then use the ultrasound to guide the needle biopsy or FNA.

In this procedure, an average of 4 needle passes (needle sticks) is needed to collect enough tissue for diagnosis. However, the number of passes can be higher or lower, depending on the individual lesion and success of the needle passes.

If participant agrees to take part in this study, 2 different needles (the standard straight hollow-core needle and the new EchoTip® Procore™ needle) will be used to sample the pancreas lesion. Two (2) passes will be performed with each needle type and compared. If additional passes are needed for diagnosis, they will not be included in this study. After the first set of needle passes, the doctor may decide that more passes are needed.

Final test results will be taken from the diagnostic results from each needle pass. The results from both types of the needle will be included in the participant's medical record.

This is an investigational study. All needles used in this study are FDA approved and commercially available. Comparing the needles is investigational.

Up to 60 participants will take part in this study. All will be enrolled at MD Anderson.

Comparison of a Novel 22-gauge Core Biopsy Needle

Prospective Comparison of a Novel 22-gauge Core Biopsy Needle With Reverse Bevel Design to a Standard Endoscopic Ultrasound (EUS) Guided Fine Needle Aspiration (FNA) Needle for Diagnosis of Solid Pancreatic Mass Lesions

The main outcome measure of the study was the diagnostic adequacy of the 22Gpc using SST and CST. The cytologic diagnostic adequacy of 22Gpc was also compared to the standard 25 G needle. Each participant underwent 4 study passes, 2 passes with a standard 25 G needle using SST, plus a random assignment to one of two groups for 2 passes with the 22Gpc (1 pass for cytologic and 1 pass for histologic analysis) using SST (group 1) or CST (group 2). Diagnostic adequacy was defined as the ability to procure cytological aspirates or histological core tissue samples that were sufficient for diagnostic interpretation.

The main outcome measure of the study was the diagnostic adequacy of the 22Gpc using SST versus CST on EUS-FNA. The cytologic diagnostic adequacy of 22Gpc was also compared to the standard 25G needle. Diagnostic adequacy was defined as the ability to procure cytological aspirates or histological core tissue samples that were sufficient for diagnostic interpretation. Two cytopathologists, blinded to needle type and technique, reviewed and graded all the study slides. Cytologic diagnostic adequacy of each pass was graded on a semiquantitative scale from 0 to 3 based on sample cellularity. A score of 2 (estimated cell count \> 500 cells) or 3 (estimated cell count \> 1000 cells) was considered adequate for diagnosis; a score of 3 was most desirable. A score \< 2 was considered inadequate. Histologic diagnostic adequacy was graded as either an adequate (score 2 or 3) or inadequate specimen for diagnosis.

The cytologic diagnostic adequacy of 22Gpc was compared to the standard 25G needle. Diagnostic adequacy was defined as the ability to procure cytological aspirates that were sufficient for diagnostic interpretation. Two cytopathologists, blinded to needle type and technique, reviewed and graded all the study slides. Cytologic diagnostic adequacy of each pass was graded on a semiquantitative scale from 0 to 3 based on sample cellularity. A score of 2 (estimated cell count \> 500 cells) or 3 (estimated cell count \> 1000 cells) was considered adequate for diagnosis; a score of 3 was most desirable. A score \< 2 was considered inadequate.

M.D. Anderson Cancer Center

Participants who are referred for EUS-FNA and consented will have their examination performed using two different needles: with the standard 22-gauge or 25-gauge straight hollow core needle

Standard Suction Technique (SST)

Capillary Suction Technique (CST)

SST: 2 passes with 25G for cytology, 1 pass each with 22Gpc for cytology and histology. Diagnostic adequacy scores compared by technique and by needle

CST: 2 passes with 25G for cytology, 1 pass each with 22Gpc for cytology and histology. Diagnostic adequacy scores compared by technique and by needle

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Weston,Brian,MD / Gastroenterology Hepatology & Nutrition

All pancreas masses: Score 0 or 1

All pancreas masses: Score 2 or 3

All pancreas masses: Score 3

Adenocarcinoma: Score 0 or 1

Adenocarcinoma: Score 2 or 3

Adenocarcinoma: Score 3

1 pass with 22Gpc for cytology, 1 pass with 22Gpc for histology using SST or CST. Diagnostic adequacy scores compared by technique for cytology and histology.

Standard Suction Technique (SST) Cytology

30 participants randomized to CST (Capillary Suction Technique)

Comparison of Diagnostic Adequacy Scores With SST vs. CST for Cytologic Diagnosis Using a 22G Core Needle.

1 pass with 22Gpc for histology using SST. Diagnostic adequacy scores compared by technique for histology.

Standard Suction Technique (SST) Histology

1 pass with 22Gpc for histology using CST. Diagnostic adequacy scores compared by technique for histology.

Capillary Suction Technique (CST) Histology

Comparison of Diagnostic Adequacy Scores With SST vs. CST for Histologic Diagnosis Using a 22G Core Needle.

All patients: comparison of diagnostic adequacy of a single pass with a 22Gpc needle versus best of 2 passes with a standard 25G needle for cytological diagnosis.

22G Procore Needle

Standard 25G Needle

Comparison of Diagnostic Adequacy of Single Pass With 22G Core Needle and Standard 25G Needle for Cytologic Diagnosis

P30 participants randomized to SST (Standard Suction Technique)

30 participants randomized to CST (Capillary Suction Technique

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer	NCT05669482	KRAS Activating... Metastatic Canc... Pancreas Cancer Neoplasms Pancr... Malignant Neopl...	avutometinib (V...	18 Years -	Verastem, Inc.
Pancreatic Cancer Dietary Assessment Study	NCT03616431	Pancreatic Neop... Pancreas Adenoc... Well-Differenti... Malignant Neopl...	Pancreo-KIT bre...	18 Years -	The Christie NHS Foundation Trust
Comparison of a Novel 22-gauge Core Biopsy Needle	NCT01598194	Solid Pancreati... Malignant Neopl...	Novel 22-gauge ...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for malignant neoplasm of pancreas