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Protocol Details

Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

13-C-0105

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: 120

Referral Letter Required

No

Population Exclusion(s)

Children

Special Instructions

Currently Not Provided

Keywords

Targeted Therapy;
Genetic Sequencing;
Advanced Cancer;
Pharmacodynamics;
Tumor Mutations

Recruitment Keyword(s)

None

Condition(s)

Neoplasms

Investigational Drug(s)

AZD1775 (MK-1775)
Veliparib (ABT-888)
Trametinib DMSO

Investigational Device(s)

None

Intervention(s)

Drug: Temozolomide
Drug: Everolimus
Drug: Carboplatin
Drug: Trametinib DMSO
Drug: ABT-888
Drug: MK-1775

Supporting Site

National Cancer Institute

Background:

- Variations in the genes in some tumors play an important role in how a cancer grows and develops. Looking at these variations and finding drugs that target them is one possible way to treat cancer. However, researchers do not yet know if this way works better than standard cancer treatments. Researchers are interested in studying people who have tumor gene variations in different types of cancer cells. They want to see if these people benefit more from being treated with a drug that specifically targets that variation than from being treated with drugs that do not. To do so, they will look at the genes from people with different sorts of cancers. Based on this analysis, they will offer treatments based on the specific gene variations found on the tumor cells.

Objectives:

- To see if choosing specific treatment options for tumor gene variations is more safe and effective than standard cancer treatments.

Eligibility:

- Individuals at least 18 years of age who have advanced solid tumors that have not responded to standard treatments.

Design:

- This study will try four different drugs or drug combinations for cancer treatment. Some of these treatments target specific tumor gene variations, while others do not. However, all drugs are intended to be used as possible cancer treatment options.

- Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and heart and lung function tests will also be performed.

- Participants will provide a tumor tissue sample for study. This sample will be used to determine possible tumor gene variations.

- Participants will be divided into groups based on their tumor gene variation. Within these groups, they will be further divided into two possible study arms. One arm will receive a drug or drug combination designed to target the tumor gene variation. The other arm will receive a drug or drug combination that is not designed to target the variation.

- Participants will receive their study drugs according to the standard dosing schedule for their treatment. Treatment will be monitored with frequent blood tests and imaging studies. If the cancer gets worse while a participant is on a study drug not designed to work on the tumor s gene variation, the study doctors may change the drug to one thought to work on that variation.

- Participants will have frequent follow-up visits to monitor the outcome of the treatment. These visits may include additional tumor biopsies.

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Eligibility

INCLUSION CRITERIA - TUMOR BIOPSY SEQUENCING:

1. Patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy and/or no standard of treatment exists that has been shown to prolong survival.

2. Patient must have tumor amenable to percutaneous or excisional skin biopsy and be willing to undergo a tumor biopsy.

3. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan.

4. Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment are eligible to participate and may continue this treatment. Patients with prostate cancer may continue LHRH agonists or antagonists.

5. Age greater than or equal to 18 years. Children are excluded from this study, but may be eligible for future pediatric trials.

6. Karnofsky performance status greater than or equal to 70%.

7. Life expectancy > 3 months.

8. Patients must have adequate organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to1,000/Microliter (mcL)

- platelets greater than or equal to100,000/Microliter (mcL)

- total bilirubin < 1.5 X institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of normal

- creatinine < 1.5 X institutional upper limit of normal

OR

- creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels greater than or equal to1.5 X institutional upper limit of normal.

- PTT less than or equal to 40 seconds unless due to lupus coagulant

9. The effects of these targeted agents on the developing human fetus are unknown or anticipated to cause fetal harm based on their mechanism of action. For this reason, women of childbearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for 3 months after completion of study. Because there may be a risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug.

10. Patients with history of CNS metastases who have received treatment and who either have not had seizures or have been on stable doses of anti-seizure medicine and had no seizures for 4 weeks will be eligible. Enzyme-inducing anticonvulsants are contraindicated.

11. Ability to understand and the willingness to sign a written informed consent document (subjects with impaired decision-making capacity are not eligible).

EXCLUSION CRITERIA - TUMOR BIOPSY SEQUENCING:

1. Women who are pregnant or breastfeeding.

2. Patients who are receiving any other investigational agents.

3. Patients with uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal infections, or active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e., quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCVRNA) are not eligible to participate. Testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated.

4. Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption,

malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with Crohn s disease or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow tablets or capsules whole. Tablets or capsules must not be crushed or chewed; nasogastric or G-tube administration is not allowed.

5. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.

6. Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic use.

INCLUSION CRITERIA - TREATMENT:

1. Patient must have predefined targeted mutation in tumor biopsy.

2. Patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy or for which no standard therapy exists that has been shown to prolong survival.

3. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan.

4. Any prior therapy, radiotherapy, or major surgery must have been completed greater than or equal to 3 weeks (> 6 weeks for nitrosoureas or mitomycin C) prior to enrollment on protocol, and the participant must have recovered to eligibility levels from prior toxicity. RFA of localized lesions should have been performed greater than or equal to 2 weeks prior to starting treatment.

5. Patients who have had prior treatment with any of the other investigational agents or combinations on this protocol are eligible but will not receive the same investigational agent (everolimus or trametinib) or combination (AZD 1775/combination or veliparib/temozolomide); instead, patients will receive an investigational agent or combination prospectively identified to work on a different target in their tumor s mutation/aberrant pathway.

6. Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment are eligible to participate and may continue this treatment. Patients with prostate cancer may continue LHRH agonists or antagonists.

7. Age greater than or equal to 18 years. 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, but may be eligible for future pediatric trials.

8. Karnofsky performance status greater than or equal to 70%.

9. Life expectancy > 3 months.

10. The effects of these targeted agents on the developing human fetus are unknown or anticipated to cause fetal harm based on their mechanism of action. For this reason, women of childbearing potential and men must agree to use highly effective contraception (see list below) prior to study entry, for the duration of study participation, and for 3 months after completion of study.

-Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]

-Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

-Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female subjects on the study, the vasectomised male partner should be the sole partner for that subject].

-Use of a combination of any two of the following (a+b or a+c or b+c):

--a.Use of oral, injected, implanted or other hormonal methods of contraception

--b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

--c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

-In case of use of oral contraception, women should have been stable on the oral agent before taking study treatment.

-Sexually active males must use a condom during intercourse

11. Because there may be a risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug.

12. Patients with melanoma and known BRAF V600E mutations must have received and progressed on specific BRAF inhibitor therapy.

13. Patients with NSCLC must have previously been tested for the presence of EGFR mutations, and, if detected, should have received and progressed on EGFR tyrosine kinase inhibitor (TKI) therapy.

14. Patients with ovarian cancer and BRCA mutations must have received specific PARP inhibitor therapy. If these patients have other mutations of interest as defined in the protocol, they will be eligible to receive agents based on that mutation.

15. Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to Trametinib DMSO, its excipients, or DMSO, are ineligible to receive treatment with Trametinib DMSO.

16. Patients with a history or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes), are ineligible to receive treatment with Trametinib DMSO. Visible retinal pathology (as assessed by ophthalmic exam) that is considered a risk factor for RVO or RPED includes evidence of new optic disc cupping or new visual field defects, or intraocular pressure > 21 mm Hg.

17. Patients with a history of seizures are not eligible to receive Veliparib, but patients with a history of CNS metastases who have received treatment and who either have not had seizures or have been on stable doses of anti-seizure medicine and had no seizures for > 4 weeks will be eligible for other study agents. Enzymeinducing anticonvulsants are contraindicated.

18. Patients who have received prior carboplatin or AZD1775 (MK-1775) would not be excluded unless the two drugs were administered in combination. Patients who have received prior carboplatin in combination with AZD1775 (MK-1775) would still be eligible to receive other study treatment regimens based on identified genetic mutation(s), other than carboplatin plus AZD1775 (MK-1775).

19. Patients who have had prior treatment with any PARP inhibitor in combination with temozolomide are ineligible to receive treatment with Veliparib on this study. Patients who have received prior temozolomide or PARP inhibitor with or without other chemotherapy/targeted agent aside from temozolomide should not be excluded solely because of receiving prior PARP inhibitor or temozolomide, unless it was in combination. Patients who have received temozolomide with a PARP inhibitor in the past are eligible to participate but will not receive Veliparib with temozolomide on study. Such patients are eligible to receive other treatment regimens on study based on identified genetic mutations.

20. Patients who have received prior everolimus or other mTOR inhibitors or those with known intolerance or hypersensitivity to other rapamycin analogs (e.g., sirolimus, temsirolimus) would not be eligible to receive everolimus on study. If these patients have mutations of interest in pathways other than the PI3K pathway as defined in the protocol, they will be eligible to receive agents based on that mutation.

21. Patients who have received prior MEK inhibitors would not be eligible to receive trametinib DMSO on study. If these patients have mutations of interest in pathways other than the RAS pathway as defined in the protocol, they will be eligible to receive agents based on that mutation.

22. Patients with current or a history of interstitial lung disease, known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air) or non-infectious pneumonitis will not be assigned treatment with everolimus or Trametinib DMSO. Symptoms should have resolved and course of antibiotics been completed for patients with a history of infectious pneumonitis to be eligible.

23. For patients on everolimus, fasting serum cholesterol less than or equal to 300 mg/dL OR less than or equal to 7.75 mmol/L AND fasting triglycerides less than or equal to 2.5x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can receive everolimus on study only after initiation of appropriate lipid lowering medication with follow up documentation of values below the above cut-off.

24. Patients with known hypersensitivity reaction to dacarbazine are ineligible to receive temozolomide.

EXCLUSION CRITERIA - TREATMENT:

1. Women who are pregnant or breastfeeding.

2. Patients who are receiving any other investigational agents.

3. Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients who have a history of seizures are not eligible to receive Veliparib, but patients who have either not had seizures or who have been on stable doses of anti-seizure medicine and had no seizures for 4 weeks will be eligible for other study agents. Enzyme-inducing anticonvulsants are contraindicated.

4. Patients with uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal infections, or active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e., quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCVRNA) are not eligible to participate. Testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated.

5. Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with Crohn s disease or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow tablets or capsules whole. Tablets or capsules must not be crushed or chewed; nasogastric or G-tube administration is not allowed.

6. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.

7. Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics (i.e., CYP450, PgP) of any of the study drugs will be determined following review of their cases by the PI. Patients on strong and moderate cytochrome P450 system inducers or inhibitors are ineligible. Every effort would be made to switch patients off medications that are known substrates of CYP450; if it is medically important for the patient to remain on such medications, these patients can still be eligible to participate based on PI discretion.

8. Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic use.

9. Patients who have poorly controlled diabetes (defined as fasting blood glucose of > 160 mg/dL (CTCAE Grade greater than or equal to 2) and HgA1c > 8% are ineligible to receive treatment with everolimus on study. Patients with fasting blood glucose > 160 mg/dL may be eligible if the HgA1c < 8%, per PI discretion.

10. Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to Trametinib DMSO, its excipients, or DMSO, are ineligible to receive Trametinib DMSO.

11. Patients requiring chronic treatment with corticosteroids or other immunosuppressive agents are ineligible to receive everolimus (topical or inhaled corticosteroids are allowed)

12. Patients who have received live attenuated vaccines within 1 week of the start are ineligible to receive everolimus.

13. Patients with a history or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes), are ineligible to receive treatment with Trametinib DMSO. Visible retinal pathology (as assessed by ophthalmic exam) that is considered a risk factor for RVO or RPED includes evidence of new optic disc cupping or new visual field defects, or intraocular pressure > 21 mm Hg.

14. Patients who have a history of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for > 3 years.

15. Patients with known hypersensitivity reaction to dacarbazine are ineligible to receive temozolomide.


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Citations:

Pallis AG, Karamouzis MV. DNA repair pathways and their implication in cancer treatment. Cancer Metastasis Rev. 2010 Dec;29(4):677-85. doi: 10.1007/s10555-010-9258-8.

Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005 Dec;4(12):988-1004. Review.

Berg JS, Khoury MJ, Evans JP. Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time. Genet Med. 2011 Jun;13(6):499-504. doi: 10.1097/GIM.0b013e318220aaba.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Alice P. Chen, M.D.
National Cancer Institute (NCI)
BG 31 RM 3A44
31 CENTER DR
BETHESDA MD 20814
(301) 496-4291
chenali@mail.nih.gov

Nancy Moore, R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 13N214
10 Center Drive
Bethesda, Maryland 20892
(301) 402-5640
nancy.moore@nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937

Clinical Trials Number:

NCT01827384

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