SWOG – EAY 131-MATCH (Molecular Analysis for Therapy Choice)
This trial aims to establish whether patients with tumor mutations, amplifications or translocations in one of the genetic pathways of interest are likely to derive clinical benefit if treated with agents targeting that specific pathway in a single-arm design.
The targets being evaluated in this study are:
MAP Kinase pathway
- mTOR: MLN0128 (on hold)
- TSC1/2: MLN0128 (on hold)
- PTEN loss: GSK2636771
- PIK3CA; GDC 0032
- AKT mutations: AZD5363
- BRAF mutations: Trametinib; Trametinib/Dabrafenib
- NRAS mutations: binimetinib
- NF1loss, GNAQ, GNA11: Trametinib
- NF2 loss: VS6063
- EGFR: afatinib, AZD9291
- HER2 mutation: afatinib,
- HER2 amplification: TDM1, herceptin/pertuzumab
- FGFR translocation/mutation/amplification: AZD4547
- C-KIT: sunitinib
- ALK translocation: crizotinib
- ROS translocation: crizotinib
- MET amplification: crizotinib
- MET exon 14 skipping: crizotinib
- Hedgehog pathway: vismodegib
- NTRK fusions: pending
- Mismatch repair: nivolumab
- CCND1, 2, 3 amplification: palbociclib
- CDK4, CDK6 amplification: pending
- DDR2 mutation: dasatinib
- Cell cycle: pending
- Patients must be ≥ 18 years of age. Because no dosing or adverse event data are currently available on the use of study investigational agents in patients < 18 years of age, children are excluded from this study
- Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration. Patients that are pregnant or breast feeding are excluded.
- Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of study.
- Patients must have histologically documented solid tumors or histologically confirmed diagnosis of lymphoma or multiple myeloma requiring therapy and that has progressed following at least one line of standard systemic therapy and/or for whose disease no standard treatment exists that has been shown to prolong survival. Patients who cannot receive other standard therapy that has been shown to prolong survival due to medical issues will be eligible, if other eligibility criteria are met or patients for whose disease no standard treatment exists that has been shown to prolong overall survival.
- NOTE: No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.
- Patients must have measurable disease.
- Patients must have tumor amenable to image guided or direct vision biopsy and be willing and able to undergo a tumor biopsy for molecular profiling. Patients with multiple myeloma other than plasmacytomas are to have a bone marrow aspirate to obtain tumor cells. Biopsy must not be considered to be more than minimal risk to the patient.
- OR Patient will be undergoing a procedure due to medical necessity during which the tissue may be collected.
- OR Formalin-fixed paraffin-embedded tumor tissue block(s) are available for submission following pre-registration (not applicable for bone marrow aspirate specimens). Criteria for the submission of FFPE tissue are:
- Tissue must have been collected within 6 months prior to pre-registration to step 0
- Patient may receive treatment after tissue
collection; however, lack of response must be documented prior to Step 1. The
following is not permitted:
- Enrollment onto another investigational study.
- Intervening therapy that constitutes a new,
molecularly targeted therapy. Please note,
immunotherapy is not considered molecularly
- Continuation of an agent/regimen for which
disease progression has been observed prior to
biopsy is permitted.
- A new immunotherapy regimen is permitted;
but, lack of response must also be documented
prior to registration to Step 0.
- Patient must not require the use of full dose coumadin-derivative anticoagulants such as warfarin. Low molecular weight heparin is permitted for prophylactic or therapeutic use.
- Patients must have ECOG performance status ≤ 1 and a life expectancy of at least 3 months.
- Patients must not currently be receiving any other investigational agents.
- Patients must not have any uncontrolled intercurrent illness including, but not limited to:
- Symptomatic congestive heart failure
- Unstable angina pectoris or coronary angioplasty, or stenting within 6 months prior to registration Step 0
- Cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE v4 Grade ≥ 2)
- Psychiatric illness/social situations that would limit compliance with study requirements
- Intra-cardiac defibrillators
- Known cardiac metastases
- Abnormal cardiac valve morphology (≥ grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study
To receive an agent, patient must not have any uncontrolled intercurrent illness such as ongoing or active infection. Patients with infections unlikely to be resolved within 2 weeks following screening should not be considered for the trial.
- Patients must be able to swallow tablets or capsules. A patient with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible.
- Patients who are HIV-positive are eligible if:
- CD4+ cell count greater or equal to 250 cells/mm3
- If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; for experimental cancer therapeutics with CYP3A/4 interactions, protease inhibitor therapy is disallowed; suggested regimens to replace protease inhibitor therapy include dolutegravir given with tenofovir/emtracitabine; raltegravir given with tenofovir and emtracitabine. Once daily combinations that use pharmacologic boosters may not be used.
- No history of non-malignancy AIDS-defining conditions other than historical low CD4+ cell counts
- Probable long-term survival with HIV if cancer were not present.
- Any prior therapy, radiotherapy (except palliative radiation therapy of 30 Gy or less), or major surgery must have been completed ≥ 4 weeks prior to treatment on MATCH and patient must be recovered from adverse events due to prior therapy (except alopecia and lymphopenia). Palliative radiation therapy must have been completed at least 2 weeks prior to enrollment on a MATCH treatment subprotocol and patient must have recovered from any adverse events of this therapy. The radiotherapy must not be to a lesion that is included as measurable disease.
- Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy ≥ 4 weeks prior to registration to Step 0.
- Patients must have discontinued steroids ≥ 1 week prior to registration to Step 0. Patients with glioblastoma (GBM) must have been on stable dose of steroids, or be off steroids, for one week prior to registration to treatment step (Step 1, 3, 5, 7).
- NOTE: The following steroids are permitted (low dose steroid use
is defined as prednisone 10 mg daily or less, or
bioequivalent dose of other corticosteroid):
- Temporary steroid use for CT imaging in setting of contrast allergy
- Low dose steroid use for appetite
- Chronic inhaled steroid use
- Steroid injections for joint disease
- Stable dose of replacement steroid for adrenal insufficiency or low
doses for non-malignant disease
- Topical steroid
- Steroids required as pre- or post-chemotherapy medication for
acceptable intervening chemotherapy
- NOTE: Steroids must be completed alongside last dose of
- Patients must have adequate organ and marrow function as defined below within 2 weeks prior to registration to Step 0 and all subsequent steps.
- Patients must have an electrocardiogram (ECG) within 8 weeks prior to registration to screening step and must have NONE of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 480 msec obtained from 3 consecutive ECGs. It is recommended that there are 10-minute (± 5 minutes) breaks between the ECGs.
- No factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
- Patients with multiple myeloma for which only bone marrow aspirates
must be submitted for screening are not eligible.
- NOTE: Patients with plasmacytoma for which FFPE or fresh biopsy tissue of the tumor will be submitted for screening are eligible.
For each agent (treatment), patients with tumors for which there is a U.S. Food and Drug Administration (FDA) approved indication, or with histologies that have been shown not to respond or not to have prolonged PFS will be ineligible.
A pre-treatment tumor biopsy and blood draw will be obtained from patients who sign the informed consent document to enroll in the study. The results of the evaluation of the biopsy specimens will determine if the patient’s tumor has an aMOI (actionable mutation of interest) for which a MATCH treatment subprotocol is available. Additionally, subsequent tumor biopsies may be taken if the patient has response and /or stable disease for more than 6 months or more at the time of the disease progression and the patient wishes to be re-evaluated for additional molecular variants.
No more than ONE mandatory biopsy and four conditional tumor biopsies will be obtained through Interventional Radiology by a percutaneous approach.
Percutaneous biopsies for accrual on the trial will be performed on patients with solid tumors or lymphomas or myeloma plasmacytomas. Bone Marrow aspirates are to be used for obtaining tumor cells in patients with myeloma. Permitted biopsy procedures should entail no more than minimal risk.
Treatment will continue until patient experiences either progression OR unacceptable toxicity OR voluntary discontinuation of treatment.
For this protocol, all patients who enroll on a treatment subprotocol, including those who discontinue protocol therapy early, will be followed for response until progression, even if non-protocol therapy is initiated, and for survival for 3 years from the date of registration (every 3 months for <
2 years and every 6 months for year 3). All patients must be followed through completion of all MATCH protocol therapy.
The investigational drug for each sub study will be provided free of charge.