TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target or to predict sensitivity to a drug. NOTE: Due to character limits, the arms section does NOT include all TAPUR Study relevant biomarkers. For additional information, contact TAPUR@asco.org, or if a patient, your nearest participating TAPUR site (see participating centers). ******************************************************************** Results in publication or poster presentation format are posted as they become available for individual cohorts at www.tapur.org/news. The results may be accessed at any time. All results will be made available on clinicaltrials.gov at the end of the study. Indexing of available results on PubMed is in progress. ********************************************************************

Detailed Description
-----------------
The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a non-randomized clinical trial that aims to describe the safety and efficacy of commercially available, targeted anticancer drugs prescribed for treatment of patients with advanced cancer that has a potentially actionable genomic variant. TAPUR will study Food and Drug Administration (FDA)-approved targeted therapies that are contributed by collaborating pharmaceutical companies, catalogue the choice of molecular profiling test by clinical oncologists and develop hypotheses for additional clinical trials.

Official Title
-----------------
Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Conditions
-----------------
Lymphoma, Non-Hodgkin, Multiple Myeloma, Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: Palbociclib
* Drug: Sunitinib
* Drug: Temsirolimus
* Drug: Trastuzumab and Pertuzumab
* Drug: Vemurafenib and Cobimetinib
* Drug: Regorafenib
* Drug: Olaparib
* Drug: Pembrolizumab
* Drug: Nivolumab and Ipilimumab
* Drug: Abemaciclib
* Drug: Talazoparib
* Drug: Atezolizumab and PHESGO
* Drug: Atezolizumab and Talazoparib
* Drug: Entrectinib
* Drug: Larotrectinib
* Drug: Tucatinib plus Trastuzumab Subcutaneous (SC)
* Drug: Futibatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 12 years of age or older (*Restrictions apply. Not all therapies are available for patients <18) Histologically-proven locally advanced or metastatic solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma who is no longer benefiting from standard anti-cancer treatment or for whom, in the opinion of the treating physician, no such treatment is available or indicated Performance status 0-2 (Per Eastern Cooperative Oncology Group (ECOG) criteria) Patients must have acceptable organ function as defined below. However, as noted above, drug-specific inclusion/exclusion criteria specified in the protocol appendix for each agent will take precedence for this and all inclusion criteria: Absolute neutrophil count ≥ 1.5 x 106/µl Hemoglobin > 9.0 g/dl Platelets > 75,000/µl Total bilirubin < 2.0 mg/ dl, except in patients with Gilbert's Syndrome Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) < 2.5 x institutional upper limit of normal (ULN) (or < 5 x ULN in patients with known hepatic metastases) Serum creatinine ≤ 1.5 × ULN or calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2 Patients must have disease that can be objectively measured by physical or radiographic exam (per RECIST v1.1 for solid tumor, Lugano criteria for non-Hodgkin lymphoma or International Myeloma Working Group criteria for multiple myeloma), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or a subcutaneous or superficial lesion that can be measured with calipers by clinical exam. For lymph nodes, the short axis must be ≥15 mm. Patient's whose disease cannot be objectively measured by physical or radiographic examination (e.g., elevated serum tumor marker only, bone-only disease without an identifiable soft tissue component, or patients with only assessable non-measurable disease) are NOT eligible. Results must be available from a genomic test or immunohistochemistry (IHC) test for protein expression performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited or New York State accredited (for labs offering services to residents of NY) laboratory. Labs that have registered the test with the NIH Genetic Testing Registry or that provide a report that has been designated as optimized for TAPUR participation are preferred, but not required. The genomic or IHC test used to qualify a patient for participation in TAPUR may have been performed on any specimen of the patient's tumor obtained at any point during the patient's care at the discretion of the patient's treating physician. Genomic assays performed on cell-free DNA in plasma (liquid biopsies) will also be acceptable if the genomic analysis is performed in a laboratory that meets the criteria described above. Ability to understand and the willingness to sign a written informed consent/assent document. Have a tumor genomic profile for which single agent treatment with one of the FDA approved targeted anti-cancer drugs included in this study has potential clinical benefit based on the criteria described in protocol. For orally administered drugs, the patient must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome. Because of the risks of drug treatment to the developing fetus, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation, and for four months following completion of study therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study or if she is the partner of a male participant in this study and becomes pregnant while he is participating in this study, she should inform her or her partner's treating physician immediately as well as her obstetrician. Female study patients who become pregnant must immediately discontinue treatment with any study therapy. Male patients should avoid impregnating a female partner. Male study patients, even if surgically sterilized, (i.e. post-vasectomy) must agree to one of the following: practice effective barrier contraception during the entire study treatment period and for a specified amount of time the last dose of study drug, or completely abstain from sexual intercourse. Note: TAPUR does not explicitly exclude any type of solid tumor, but the patient must have measurable and evaluable disease per RECIST v1.1. Exclusion Criteria: Patients whose disease is not measurable or cannot be assessed by radiographic imaging or physical examination (e.g., elevated serum tumor marker only) are not eligible Patients with primary brain tumors or leptomeningeal metastases are excluded. Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to registration. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month prior to study enrollment. Patients with known progressive brain metastases are eligible but additional eligibility criteria apply. Note: there are additional exclusion criteria that may apply

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 4 (CDKN2A, CDK4, CDK6)<br>Participants receive palbociclib - dosage, frequency and duration per label; acceptable genomic matches include CDKN2A loss or mutation, CDK4, CDK6 amplifications, CDKN2B loss or mutation | Drug: Palbociclib<br>* drug<br>* Other names: Ibrance;|
| Other: Group 5 (CSF1R,PDGFR,VEGFR)<br>Participants receive sunitinib - dosage, frequency and duration per label; acceptable genomic matches include CSF1R, PDGFR, VEGFR1/2/3, KIT, FLT-3, RET, FGFR1/2/3, VHL amplifications or mutations | Drug: Sunitinib<br>* drug<br>* Other names: Sutent;|
| Other: Group 6 (mTOR, TSC)<br>Participants receive temsirolimus - dosage, frequency and duration per label; acceptable genomic matches include mTOR, TSC1/2, AKT1 mutations | Drug: Temsirolimus<br>* drug<br>* Other names: Torisel;|
| Other: Group 8 (ERBB2)<br>Participants receive trastuzumab and pertuzumab - dosage, frequency and duration per label; acceptable genomic matches include ERBB2 amplification or overexpression, and specific ERBB2 mutations | Drug: Trastuzumab and Pertuzumab<br>* drug<br>* Other names: Herceptin and Perjeta;|
| Other: Group 9 (BRAF V600E/D/K/R)<br>Participants receive vemurafenib and cobimetinib - dosage, frequency and duration per label; acceptable genomic matches include BRAF V600E/D/K/R mutations | Drug: Vemurafenib and Cobimetinib<br>* drug<br>* Other names: Zelboraf and Cotellic;|
| Other: Group 13 (RET,VEGFR1/2/3,KIT,PDGFRβ,RAF-1,BRAF)<br>Participants receive regorafenib - dosage, frequency and duration per label; acceptable genomic matches include RET, VEGFR1/2/3, KIT, PDGFRβ, RAF-1, BRAF mutations or amplifications | Drug: Regorafenib<br>* drug<br>* Other names: Stivarga;|
| Other: Group 14 (BRCA1/2; ATM)<br>Participants receive olaparib - dosage, frequency and duration per label; acceptable genomic matches include germline or somatic BRCA1/2 inactivating mutations; ATM mutations or deletions | Drug: Olaparib<br>* drug<br>* Other names: Lynparza;|
| Other: Group 15 (POLE, POLD1)<br>Participants receive pembrolizumab - dosage, frequency and duration per label; acceptable genomic matches include specific POLE and POLD1 mutations | Drug: Pembrolizumab<br>* drug<br>* Other names: Keytruda;|
| Other: Group 16 (MSI-H, high mutational load and others)<br>Participants receive nivolumab and ipilimumab - dosage, frequency and duration per label; acceptable genomic matches include MSI high status, high tumor mutational burden, MLH1, MSH2/6, PMS2, EPCAM mutations, specific POLE or POLD1 mutations, BRCA1/2, ATM, MSH3, PMS1, MLH3, EXO1, RFC1/2/3/4/5, PCNA, RPA1/2/3/4, and SSBP1 loss of function mutations | Drug: Nivolumab and Ipilimumab<br>* drug<br>* Other names: Opdivo and Yervoy;|
| Other: Group 17 (CDKN2A, CDK4, CDK6)<br>Participants receive abemaciclib - dosage, frequency and duration per label; acceptable genomic matches include CDKN2A loss or mutation, CDK4, CDK6 amplifications, CDKN2B loss or mutation | Drug: Abemaciclib<br>* drug<br>* Other names: Verzenio;|
| Other: Group 19 (BRCA1/2, PALB2)<br>Participants receive talazoparib - dosage, frequency and duration per label; acceptable genomic matches include germline or somatic BRCA1/2 and PALB2 mutations | Drug: Talazoparib<br>* drug<br>* Other names: Talzenna;|
| Other: Group 20 (ERBB2)<br>Participants receive atezolizumab plus PHESGO - dosage, frequency and duration per label; acceptable genomic matches include ERBB2 amplification or overexpression | Drug: Atezolizumab and PHESGO<br>* drug<br>* Other names: Tecentriq and PHESGO;|
| Other: Group 21 (BRCA1/2, PALB2, ATM, and others)<br>Participants receive atezolizumab plus talazoparib - dosage, frequency and duration per label; acceptable genomic matches include germline or somatic mutations in BRCA1/2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12; positive genomic instability score reported on the Myriad MyChoice CDx test; or Genomic Loss of Heterozygosity (LOH) Score above threshold as reported on a FoundationOne CDx test or another qualifying test for TAPUR with MTB approval | Drug: Atezolizumab and Talazoparib<br>* drug<br>* Other names: Tecentriq and Talzenna;|
| Other: Group 22 (ROS1 fusion)<br>Participants receive entrectinib - dosage, frequency and duration per label; acceptable genomic matches include any ROS1 fusion | Drug: Entrectinib<br>* drug<br>* Other names: Rozlytrek;|
| Other: Group 23 (NTRK amplification)<br>Participants receive larotrectinib - dosage, frequency and duration per label; acceptable genomic matches include NTRK1/2/3 amplification | Drug: Larotrectinib<br>* drug<br>* Other names: Vitrakvi;|
| Other: Group 24 (ERBB2)<br>Participants receive tucatinib plus trastuzumab SC - dosage, frequency and duration per label; acceptable genomic matches include ERBB2 amplification or overexpression, and specific ERBB2 mutations | Drug: Tucatinib plus Trastuzumab Subcutaneous (SC)<br>* drug<br>* Other names: Tukysa and Herceptin Hylecta;|
| Other: Group 25<br>Participants receive futibatinib- dosage, frequency and duration per label; acceptable genomic matches include FGFR 1,2,3,4 fusion (or other rearrangement) or mutation | Drug: Futibatinib<br>* drug<br>* Other names: Lytgobi;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate defined as % of participants in a cohort with complete or partial response or with stable disease according to standard response criteria | Each cohort includes participants with the same tumor type, genomic variant and study drug. For solid tumors, the Response Evaluation Criteria for Solid Tumors (RECIST) criteria will be used, for non-Hodgkin Lymphoma, the Lugano Criteria will be used, and for multiple myeloma, the International Uniform Response Criteria for Multiple Myeloma will be used. | Assessed at 16 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS will be estimated using the Kaplan-Meier method | Duration of survival from registration on study until death from any cause, assessed throughout end of study, up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cancer, precision medicine, targeted therapy, off-label