Advanced Malignant Solid Neoplasm
Conditions
Brief summary
This phase II trial studies molecular profiling-based assignment of cancer therapy (MPACT) in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Adavosertib, everolimus, and trametinib are drugs that each target a specific variation in tumors by blocking different proteins needed for cell growth. Veliparib blocks an enzyme that helps repair deoxyribonucleic acid (DNA) damaged by chemotherapy, which may help chemotherapy drugs work better. It is not yet known whether testing patients for variations in their tumor and assigning treatment targeting the variation is more effective than standard non-targeted therapy in treating advanced solid tumors.
Detailed description
PRIMARY OBJECTIVE: I. Evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers. OUTLINE: Patients are assigned to 1 of 4 treatment regimens corresponding to one of their mutation/amplification categories. REGIMEN I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and temozolomide PO once daily (QD) on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. REGIMEN II: Patients receive adavosertib PO BID for 5 doses starting on day 1 and carboplatin intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018) REGIMEN III: Patients receive everolimus PO every day (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018) REGIMEN IV: Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018) After completion of study treatment, patients are followed up for 30 days. Patients with unacceptable toxicities that have not resolved by day 30 are followed up biweekly until stabilization or resolution.
Interventions
DRUGAdavosertib
Given by mouth (PO)
DRUGCarboplatin
Given intravenous (IV)
DRUGEverolimus
Given by mouth (PO)
DRUGTemozolomide
Given by mouth (PO)
DRUGTrametinib
Given by mouth (PO)
DRUGVeliparib
Given by mouth (PO)
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* TUMOR BIOPSY SEQUENCING: 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 * TUMOR BIOPSY SEQUENCING: Patient must have tumor amenable to percutaneous or excisional skin biopsy and be willing to undergo a tumor biopsy or biopsy samples (formalin-fixed paraffin-embedded \[FFPE\] blocks) collected on another study or from a procedure performed due to medical necessity may be acceptable if collected within 6 months prior to registration on molecular profiling-based assignment of cancer therapy (MPACT) and providing that the patient has not received any investigational or targeted treatment since that time, or a report from a Molecular Analysis for Therapy Choice (MATCH) study designated Clinical Laboratory Improvement Act (CLIA) laboratory that a patient has a variant in the genes of interest * TUMOR BIOPSY SEQUENCING: 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 \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan * TUMOR BIOPSY SEQUENCING: Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment, denosumab, or similar agents are eligible to participate and may continue this treatment; patients with prostate cancer may continue luteinizing hormone-releasing hormone (LHRH) agonists or antagonists * TUMOR BIOPSY SEQUENCING: Karnofsky performance status \>= 70% * TUMOR BIOPSY SEQUENCING: Life expectancy \> 3 months * TUMOR BIOPSY SEQUENCING: Absolute neutrophil count \>= 1,000/uL (mcL) * TUMOR BIOPSY SEQUENCING: Platelets \>= 100,000/uL (mcL) * TUMOR BIOPSY SEQUENCING: Total bilirubin \< 1.5 x institutional upper limit of normal * TUMOR BIOPSY SEQUENCING: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional upper limit of normal * TUMOR BIOPSY SEQUENCING: Creatinine \< 1.5 x institutional upper limit of normal OR creatinine clearance \>= 60 mL/min for patients with creatinine levels \>= 1.5 x institutional upper limit of normal * TUMOR BIOPSY SEQUENCING: 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 * TUMOR BIOPSY SEQUENCING: Patients with history of central nervous system (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 * TUMOR BIOPSY SEQUENCING: Ability to understand and the willingness to sign a written informed consent document (subjects with impaired decision-making capacity are not eligible) * TREATMENT: Patient must have predefined targeted mutation in tumor biopsy * TREATMENT: 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 * TREATMENT: 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 \>= 20 mm with conventional techniques or as \>= 10 mm with spiral CT scan * TREATMENT: Any prior therapy, radiotherapy, or major surgery must have been completed \>= 3 weeks (\> 6 weeks for nitrosoureas or mitomycin C) or 5 half-lives of the agent (whichever is shorter) prior to enrollment on protocol, and the participant must have recovered to eligibility levels from prior toxicity; radiofrequency ablation (RFA) of localized lesions should have been performed \>= 2 weeks prior to treatment * TREATMENT: Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment, denosumab, or similar agents are eligible to participate and may continue this treatment; patients with prostate cancer may continue LHRH agonists or antagonists * TREATMENT: Karnofsky performance status \>= 70% * TREATMENT: Absolute neutrophil count \>= 1,000/uL (mcL) * TREATMENT: Platelets \>= 100,000/uL (mcL) * TREATMENT: Total bilirubin \< 1.5 x institutional upper limit of normal * TREATMENT: AST (SGOT)/ALT (SGPT) =\< 3 x institutional upper limit of normal * TREATMENT: Creatinine \< 1.5 x institutional upper limit of normal OR creatinine clearance \>= 60 mL/min for patients with creatinine levels \>= 1.5 x institutional upper limit of normal * TREATMENT: Life expectancy \> 3 months * TREATMENT: 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 vasectomized male partner should be the sole partner for that subject); use of a combination of any two of the following: * Use of oral, injected, implanted or other hormonal methods of contraception * Placement of an intrauterine device (IUD) or intrauterine system (IUS) * 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 * TREATMENT: 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 * TREATMENT: Patients with ovarian cancer or metastatic breast cancer and breast cancer gene (BRCA) mutations must have received approved poly (ADP-ribose) polymerase (PARP) inhibitor therapy; these patients are eligible for the veliparib plus temozolomide arm unless the PARP inhibitor was administered with temozolomide * TREATMENT: Patients with a history of seizures are not eligible to receive veliparib * TREATMENT: Patients who have had prior treatment with any PARP inhibitor in combination with temozolomide are not eligible to receive treatment with veliparib on this study; patients who have received prior temozolomide or PARP inhibitor with or without other chemotherapy/targeted agent should not be excluded * TREATMENT: Patients must have \>= 10.0 g/dL hemoglobin (Hb) and no blood transfusion in the past 28 days to receive veliparib
Exclusion criteria
* TUMOR BIOPSY SEQUENCING: Women who are pregnant or breastfeeding * TUMOR BIOPSY SEQUENCING: Patients who are receiving any other investigational agents; patients on other trials will be eligible as long as they are no longer receiving study treatment * TUMOR BIOPSY SEQUENCING: 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 hepatitis B virus \[HBV\]-DNA and/or positive hepatitis B surface antigen \[HbsAg\], quantifiable hepatitis C virus \[HCV\]-ribonucleic acid \[RNA\]) are not eligible to participate; testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated * TUMOR BIOPSY SEQUENCING: 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 gastrostomy tube (G-tube) administration is not allowed * TUMOR BIOPSY SEQUENCING: Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic (PK) interactions * TUMOR BIOPSY SEQUENCING: Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded; low molecular weight heparin is permitted for prophylactic or therapeutic use * TUMOR BIOPSY SEQUENCING: Patients who have previously been treated with the combination of temozolomide plus a PARP inhibitor should not be considered eligible for a biopsy given that these patients would not be eligible for the active veliparib plus temozolomide arm * TREATMENT: Women who are pregnant or breastfeeding * TREATMENT: Patients who are receiving any other investigational agents; patients on other trials will be eligible as long as they are no longer receiving study treatment * TREATMENT: 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 * TREATMENT: 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 hepatitis B virus (HBV)-DNA and/or positive hepatitis B surface antibody (HbsAg), quantifiable hepatitis C virus (HCV)-RNA) are not eligible to participate; testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated * TREATMENT: 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 intravenous (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 * TREATMENT: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions * TREATMENT: Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics (i.e., cytochrome P450, family 3, subfamily A, polypeptide 4 \[CYP450\], P-glycoprotein \[PgP\]) of any of the study drugs will be determined following review of their cases by the principal investigator (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 * TREATMENT: Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded; low molecular weight heparin is permitted for prophylactic or therapeutic use * TREATMENT: 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 * TREATMENT: Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing veliparib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Objective Response | Up to 30 days after completion of study treatment, up to 75 months | ORR is the proportion of participants with a complete response (CR) or partial response (PR) per the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all tumors. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With 4 Month Progression-free Survival (PFS) | 4 months | Time from random assignment to progression or death from any cause (whichever comes first). Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions is also considered progressions. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | Date treatment consent signed to date off study, approx. 73months (m) & 21day (d); 4m & 11d; 61m & 8d; 4m & 11d; 10m & 11d; 72m & 29d; 13m & 11d; 6m & 13d; 29m & 18d; 48m & 25d; 49m & 5d; 4m &7d; 15m & 5d; and 75m &13d, for each group respectively. | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Assignment Code 1 (TAC1) TAC1: Veliparib (ABT-888) 40mg by mouth (PO) twice a day (BID) on days 1-7; Temozolomide 150 mg/m\^2 PO every day (QD) on days 1-5 | 13 |
| TAC1 -> TAC4 TAC1: Veliparib (ABT-888) 40mg by mouth (PO) twice a day (BID) on days 1-7; Temozolomide 150 mg/m\^2 PO every day (QD) on days 1-5 TAC4: Adavosertib (MK-1775) 225 mg by mouth (PO) twice a day (BID) x 5 doses on days 1-3; Carboplatin area under the concentration (AUC) 5 intravenous (IV) over 30 min on day 1 | 1 |
| TAC2 TAC2: Everolimus 10 mg by mouth (PO) every day (QD) | 9 |
| TAC2 -> TAC1 TAC2: Everolimus 10 mg by mouth (PO) every day (QD) TAC1: Veliparib (ABT-888) 40mg by mouth (PO) twice a day (BID) on days 1-7; Temozolomide 150 mg/m\^2 PO every day (QD) on days 1-5 | 1 |
| TAC2 -> TAC3 TAC2: Everolimus 10 mg by mouth (PO) every day (QD) TAC3: Trametinib 2mg by mouth (PO) every day (QD) | 1 |
| TAC3 TAC3: Trametinib 2mg by mouth (PO) every day (QD) | 22 |
| TAC3 -> TAC1 TAC3: Trametinib 2mg by mouth (PO) every day (QD) TAC1: Veliparib (ABT-888) 40mg by mouth (PO) twice a day (BID) on days 1-7; Temozolomide 150 mg/m\^2 PO every day (QD) on days 1-5 | 2 |
| TAC3 -> TAC1 -> TAC4 TAC3: Trametinib 2mg by mouth (PO) every day (QD) TAC1: Veliparib (ABT-888) 40mg by mouth (PO) twice a day (BID) on days 1-7; Temozolomide 150 mg/m\^2 PO every day (QD) on days 1-5 TAC4: Adavosertib (MK-1775) 225 mg by mouth (PO) twice a day (BID) x 5 doses on days 1-3; Carboplatin area under the concentration (AUC) 5 intravenous (IV) over 30 min on day 1 | 1 |
| TAC3 -> TAC4 TAC3: Trametinib 2mg by mouth (PO) every day (QD) TAC4: Adavosertib (MK-1775) 225 mg by mouth (PO) twice a day (BID) x 5 doses on days 1-3; Carboplatin area under the concentration (AUC) 5 intravenous (IV) over 30 min on day 1 | 2 |
| TAC4 TAC4: Adavosertib (MK-1775) 225 mg by mouth (PO) twice a day (BID) x 5 doses on days 1-3; Carboplatin area under the concentration (AUC) 5 intravenous (IV) over 30 min on day 1 | 15 |
| TAC4 -> TAC1 TAC4: Adavosertib (MK-1775) 225 mg by mouth (PO) twice a day (BID) x 5 doses on days 1-3; Carboplatin area under the concentration (AUC) 5 intravenous (IV) over 30 min on day 1 TAC1: Veliparib (ABT-888) 40mg by mouth (PO) twice a day (BID) on days 1-7; Temozolomide 150 mg/m\^2 PO every day (QD) on days 1-5 | 7 |
| TAC4 -> TAC2 TAC4: Adavosertib (MK-1775) 225 mg by mouth (PO) twice a day (BID) x 5 doses on days 1-3; Carboplatin area under the concentration (AUC) 5 intravenous (IV) over 30 min on day 1 TAC2: Everolimus 10 mg by mouth (PO) every day (QD) | 1 |
| TAC4 -> TAC3 TAC4: Adavosertib (MK-1775) 225 mg by mouth (PO) twice a day (BID) x 5 doses on days 1-3; Carboplatin area under the concentration (AUC) 5 intravenous (IV) over 30 min on day 1 TAC3: Trametinib 2mg by mouth (PO) every day (QD) | 2 |
| Participants Enrolled But Not Treated Participants who signed consent and were enrolled but not treated. | 131 |
| Total | 208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Disease progression before treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 |
| Overall Study | Ineligible | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 19 |
| Overall Study | Insufficient tumor cells | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 13 |
| Overall Study | No actionable mutation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 73 |
| Overall Study | Participant declined to participate (before treatment started) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 15 |
| Overall Study | Participant died before treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 |
| Overall Study | Switched to alternative treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | TAC1 -> TAC4 | TAC2 | TAC2 -> TAC1 | TAC2 -> TAC3 | TAC3 | TAC3 -> TAC1 | TAC3 -> TAC1 -> TAC4 | Treatment Assignment Code 1 (TAC1) | TAC3 -> TAC4 | TAC4 | TAC4 -> TAC1 | TAC4 -> TAC2 | TAC4 -> TAC3 | Participants Enrolled But Not Treated | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 9 Participants | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants | 42 Participants | 69 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 6 Participants | 1 Participants | 1 Participants | 13 Participants | 2 Participants | 1 Participants | 6 Participants | 2 Participants | 11 Participants | 3 Participants | 1 Participants | 2 Participants | 89 Participants | 139 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 0 | 54 years STANDARD_DEVIATION 15.15 | 59.1 years STANDARD_DEVIATION 0 | 59 years STANDARD_DEVIATION 0 | 58 years STANDARD_DEVIATION 12.22 | 54 years STANDARD_DEVIATION 9.9 | 45 years STANDARD_DEVIATION 0 | 61 years STANDARD_DEVIATION 15.15 | 55.95 years STANDARD_DEVIATION 7 | 59 years STANDARD_DEVIATION 10.54 | 63.2 years STANDARD_DEVIATION 13.72 | 39 years STANDARD_DEVIATION 0 | 61.65 years STANDARD_DEVIATION 4.03 | 58 years STANDARD_DEVIATION 11.53 | 57.75 years STANDARD_DEVIATION 11.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 11 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 8 Participants | 1 Participants | 1 Participants | 19 Participants | 2 Participants | 1 Participants | 13 Participants | 2 Participants | 14 Participants | 7 Participants | 1 Participants | 2 Participants | 117 Participants | 189 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 4 Participants |
| Karnofsky Performance Status 100 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 6 Participants | 11 Participants |
| Karnofsky Performance Status 70 | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants | 11 Participants |
| Karnofsky Performance Status 80 | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 6 Participants | 2 Participants | 0 Participants | 1 Participants | 41 Participants | 67 Participants |
| Karnofsky Performance Status 90 | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 14 Participants | 2 Participants | 0 Participants | 8 Participants | 0 Participants | 8 Participants | 4 Participants | 1 Participants | 1 Participants | 76 Participants | 119 Participants |
| Participants with an Actionable Mutation of Interest (aMOI) in a Targeted Pathway Deoxyribonucleic acid (DNA) repair | 1 Participants | 5 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 9 Participants | 1 Participants | 11 Participants | 7 Participants | 0 Participants | 1 Participants | 21 Participants | 62 Participants |
| Participants with an Actionable Mutation of Interest (aMOI) in a Targeted Pathway No aMOI detected | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 93 Participants | 93 Participants |
| Participants with an Actionable Mutation of Interest (aMOI) in a Targeted Pathway P13K | 0 Participants | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 15 Participants |
| Participants with an Actionable Mutation of Interest (aMOI) in a Targeted Pathway RAS/RAF/MEK | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 17 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 13 Participants | 38 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 9 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 19 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 11 Participants |
| Race (NIH/OMB) White | 1 Participants | 8 Participants | 1 Participants | 1 Participants | 15 Participants | 2 Participants | 1 Participants | 11 Participants | 2 Participants | 9 Participants | 5 Participants | 1 Participants | 2 Participants | 95 Participants | 154 Participants |
| Region of Enrollment United States | 1 participants | 9 participants | 1 participants | 1 participants | 22 participants | 2 participants | 1 participants | 13 participants | 2 participants | 15 participants | 7 participants | 1 participants | 2 participants | 131 participants | 208 participants |
| Sex: Female, Male Female | 0 Participants | 6 Participants | 1 Participants | 1 Participants | 12 Participants | 1 Participants | 0 Participants | 9 Participants | 2 Participants | 13 Participants | 3 Participants | 1 Participants | 0 Participants | 67 Participants | 116 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 10 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 2 Participants | 4 Participants | 0 Participants | 2 Participants | 64 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 13 | 0 / 1 | 3 / 9 | 0 / 1 | 0 / 1 | 1 / 22 | 0 / 2 | 0 / 1 | 0 / 2 | 1 / 15 | 1 / 7 | 0 / 1 | 0 / 2 | 5 / 131 |
| other Total, other adverse events | 13 / 13 | 1 / 1 | 9 / 9 | 1 / 1 | 1 / 1 | 22 / 22 | 2 / 2 | 1 / 1 | 2 / 2 | 15 / 15 | 7 / 7 | 1 / 1 | 2 / 2 | 2 / 131 |
| serious Total, serious adverse events | 5 / 13 | 0 / 1 | 4 / 9 | 1 / 1 | 0 / 1 | 11 / 22 | 1 / 2 | 1 / 1 | 1 / 2 | 10 / 15 | 4 / 7 | 1 / 1 | 2 / 2 | 10 / 131 |
Outcome results
Primary
Number of Participants With an Objective Response
ORR is the proportion of participants with a complete response (CR) or partial response (PR) per the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all tumors. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: Up to 30 days after completion of study treatment, up to 75 months
Population: Participants enrolled but not treated were not applicable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Assignment Code 1 (TAC1) | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| Treatment Assignment Code 1 (TAC1) | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC1 -> TAC4 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC1 -> TAC4 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC2 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC2 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC2 -> TAC1 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC2 -> TAC1 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC2 -> TAC3 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC2 -> TAC3 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC3 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC3 | Number of Participants With an Objective Response | Partial Response | 1 Participants |
| TAC3 -> TAC1 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC3 -> TAC1 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC3 -> TAC1 -> TAC4 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC3 -> TAC1 -> TAC4 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC3 -> TAC4 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC3 -> TAC4 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC4 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC4 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC4 -> TAC1 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC4 -> TAC1 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC4 -> TAC2 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
| TAC4 -> TAC2 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC4 -> TAC3 | Number of Participants With an Objective Response | Partial Response | 0 Participants |
| TAC4 -> TAC3 | Number of Participants With an Objective Response | Complete Response | 0 Participants |
Secondary
Proportion of Participants With 4 Month Progression-free Survival (PFS)
Time from random assignment to progression or death from any cause (whichever comes first). Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions is also considered progressions.
Time frame: 4 months
Population: Participants enrolled but not treated were not applicable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Assignment Code 1 (TAC1) | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.23 proportion of participants |
| TAC1 -> TAC4 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.00 proportion of participants |
| TAC2 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.22 proportion of participants |
| TAC2 -> TAC1 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.00 proportion of participants |
| TAC2 -> TAC3 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 1.00 proportion of participants |
| TAC3 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.41 proportion of participants |
| TAC3 -> TAC1 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.50 proportion of participants |
| TAC3 -> TAC1 -> TAC4 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.00 proportion of participants |
| TAC3 -> TAC4 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.00 proportion of participants |
| TAC4 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.13 proportion of participants |
| TAC4 -> TAC1 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.29 proportion of participants |
| TAC4 -> TAC2 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.00 proportion of participants |
| TAC4 -> TAC3 | Proportion of Participants With 4 Month Progression-free Survival (PFS) | 0.00 proportion of participants |
Other Pre-specified
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Date treatment consent signed to date off study, approx. 73months (m) & 21day (d); 4m & 11d; 61m & 8d; 4m & 11d; 10m & 11d; 72m & 29d; 13m & 11d; 6m & 13d; 29m & 18d; 48m & 25d; 49m & 5d; 4m &7d; 15m & 5d; and 75m &13d, for each group respectively.
Population: Adverse events were collected for participants that were enrolled but not treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Assignment Code 1 (TAC1) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 13 Participants |
| TAC1 -> TAC4 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 1 Participants |
| TAC2 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 9 Participants |
| TAC2 -> TAC1 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 1 Participants |
| TAC2 -> TAC3 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 1 Participants |
| TAC3 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 22 Participants |
| TAC3 -> TAC1 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 2 Participants |
| TAC3 -> TAC1 -> TAC4 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 1 Participants |
| TAC3 -> TAC4 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 2 Participants |
| TAC4 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 15 Participants |
| TAC4 -> TAC1 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 7 Participants |
| TAC4 -> TAC2 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 1 Participants |
| TAC4 -> TAC3 | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 2 Participants |
| Participants Enrolled But Not Treated | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) | 2 Participants |