Patient case: 56-year-old female with basal cell carcinoma; genetic feature: PTCH1

Clinical trial: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, and Erivedge Treatment Targeted Against Certain Mutations in Cancer Patients

Summary: This is a multicenter, non-randomized, open-label study designed to evaluate four treatment regimens in patients with advanced cancer for whom there is no available, beneficial treatment. Patients with HER2 overexpression, amplification, or -activating mutation will be treated with Herceptin/Perjeta; those with epidermal growth factor receptor (EGFR), with Tarceva; those with BRAF-activating mutation, with Zelboraf/Cotellic; and those with Hedehog pathway potentially clinically relevant mutation, with Erivedge. Treatment will continue until disease progression or unacceptable toxicity occurs. Study is expected to last up to 5 years.


Eligibility: Inclusion Criteria:
  -  Age >/= 18 years
  -  Life expectancy >/= 12 weeks
  -  Histologically documented metastatic cancer (solid tumors, not including hematologic malignancies)
  -  Molecular testing results from certified laboratories (using tissue from the most recent tumor biopsy in the metastatic setting) that show at least one of the following abnormalities:
  -  HER2 overexpression, amplification, or HER2-activating mutation
  -  EGFR-activating mutation
  -  BRAF-activating mutation
  -  Hedgehog pathway potentially clinically relevant mutation (activating mutation of SMO or loss-of-function mutation of PTCH-1)
  -  Patients who have received standard first-line therapy for metastatic cancer (except for the tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is considered the best available treatment option. Eligible patients should not have available therapies that will convey clinical benefit.
  -  No previous treatment with the specific assigned study drug or any other drug sharing the same target
  -  Progressive cancer at the time of study entry
  -  Measurable or evaluable disease by RECIST v. 1.1
  -  Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2
  -  Adequate hematologic, renal, and liver function
  -  Use of effective contraception as defined by the protocol
  Study-drug specific criteria:
  -  Trastuzumab plus Pertuzumab
  -  Patients with solid tumors that have HER2 overexpression, amplification, or HER2-activating mutation
  -  Patients with breast, gastric, or gastroesophageal junction cancer must have HER2-activating mutation.
  -  Left ventricular ejection fraction (LVEF) > 50% or above the lower limit of the institutional normal range, whichever is lower
  -  Erlotinib
  -  Patients with solid tumors that harbor EGFR-activating mutations
  -  Vemurafenib
  -  BRAF mutation positivity as determined by next generation sequencing (NGS) or real time-polymerase chain reaction (RT-PCR) will be accepted.
  -  Vismodegib
  -  Hedgehog-activating mutation positivity
  -  All non-hematological adverse events related to any prior chemotherapy, surgery, or radiotherapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade </= 2 prior to starting therapy.
  Exclusion Criteria:
  -  Patients with hematologic malignancies
  -  Concurrent administration of any other anti-cancer therapy (except male patients with prostate cancer receiving androgen blockade)
  -  Bisphosphonates and denosumab are allowed.
  -  Most recent anti-cancer therapy </= 28 days and have not recovered from the side effects, excluding alopecia
  -  Radiaiton therapy within ≤ 14 days
  -  Active or untreated brain metastases
  -  History of carcinomatous meningitis
  -  Uncontrolled concurrent malignancy (early stage is allowed if not requiring active therapy or intervention)
  -  Women who are breastfeeding or pregnant
  -  Any significant cardiovascular events within 6 months prior to study entry.
  -  Pulmonary embolism within 30 days prior to study entry
  -  History or presence of clinically significant ventricular or atrial dysrhythmia >Grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI CTCAE v4.0])
  -  Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality
  -  Eligible for another actively accruing Roche/Genentech-sponsored interventional clinical trial
  Study-drug specific criteria:
  -  Trastuzumab plus Pertuzumab
  -  Breast, gastric, or gastroesophageal junction cancer identified by HER2 amplification or overexpression
  -  Previous treatment with any HER2-targeted therapy
  -  Erlotinib
  -  Non-small cell lung cancer (NSCLC) or pancreatic cancer identified by exon 19 and exon 21 mutations
  -  Cancers with exon 20 mutations
  -  Previous treatment with erlotinib or any other EGFR inhibitor
  -  Vemurafenib plus Cobimetinib
  -  Malignant melanoma, papillary thyroid cancer, colorectal cancer, or hematologic malignancy including multiple myeloma
  -  Left ventricular ejection fraction (LVEF) below institutional lower level of normal (LLN) or below 50%, whichever is lower
  -  History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration
  -  Presence of any of the following condition, which are risk factors for RVO: Uncontrolled glaucoma with intraocular pressure >21 mm Hg, Serum cholesterol >/= Grade 2, Hypertriglyceridemia >/= Grade 2, and Hyperglycemia (fasting) >/= Grade 2
  -  Prior or concurrent malignancy with known RAS mutation
  -  Previous treatment with vemurafenib or any other BRAF inhibitor (prior sorafenib is allowed)
  -  Previous treatment with cobimetinib or any other RAF inhibitor
  -  Prior treatment with a MEK inhibitor
  -  Corrected QT (QTc) interval ≥450 msec at baseline or history of congenital long QT syndrome
  -  Vismodegib
  -  Basal cell carcinoma of the skin, medulloblastoma, small-cell lung cancer, or hematologic malignancies
  -  Previous treatment with vismodegib or any other hedgehog pathway inhibitor
  -  Breast cancer patients taking hormone replacement therapy or hormonal birth control

Relevance to patient case: possibly relevant