Phase 0 - Open label, Single dose study of siG12D LODER in Patients with operable adenocarcinoma of the pancreas. The primary endpoint: To assess efficacy and local distribution of siRNA out of eight high dose siG12D LODERs in patients diagnosed with operable adenocarcinoma of the pancreas. The Secondary endpoint: Short term tolerability and safety assessment Phase I - This study is designed to investigate the safety of siG12D LODER (Local Drug EluteR) in patients diagnosed with adenocarcinoma of the pancreas. The primary endpoint: To asses efficacy of siG12D LODER and local distribution in non-operable patients by histopathology measurements, local distribution by RNA analysis. To define the dose-limiting toxicities (DLT) The Secondary endpoint 1. To determine the recommended Phase II dose (RP2D) 2. To define and maximum tolerated dose (MTD) 3. In the event of surgery, assessment of siG12D LODER local distribution and efficacy will be based on histopathology measurements and RNA analysis. 4. Progression free survival - only by long term follow-up

NCT01188785

Conditions

1. Pancreatic Ductal Adenocarcinoma
2. Pancreatic Cancer

Interventions

1. Drug: siG12D LODER

MeSH:Adenocarcinoma Pancreatic Neoplasms

HPO:Neoplasm of the pancreas

The majority of pancreatic ductal adenocarcinomas involve mutations in the KRAS oncogene (the most common is G12D), therefore stable administration of KRASG12D siRNA has the potential to silence and lead to apoptosis of such cancer cells and thereby slow and even halt the tumor growth. --- G12D ---

The goal of this multicenter prospective study is to validate, and ultimately translate in routine clinical practice, the use of plasma analysis of ccfDNA for the determination of KRAS mutation status in mCRC patients.

NCT02784639

Conditions

1. Colorectal Cancer

Interventions

1. Other: Plasma Analysis of circulating cell free DNA
2. Other: Tumor tissue analysis of circulating cell free DNA

MeSH:Colorectal Neoplasms

HPO:Neoplasm of the large intestine

As a consequence, the method was adapted to detect the six more frequent KRAS mutations in CRC (G12D, G12V, G13D, G12S, G12C, G12A) and the BRAF V600E. --- G12D ---

The investigational drug to be studied in this protocol, BCA101, is a first-in-class compound that targets both EGFR with TGFβ. Based on preclinical data, this bifunctional antibody may exert synergistic activity in patients with EGFR-driven tumors.

NCT04429542

Conditions

1. TNBC - Triple-Negative Breast Cancer
2. Head and Neck Squamous Cell Carcinoma
3. Squamous Cell Carcinoma of Anal Canal
4. Uveal Melanoma
5. Glioblastoma
6. Colorectal Cancer
7. Chordoma
8. Squamous Cell Carcinoma of the Lung
9. KRAS G12D
10. KRAS G13D
11. EGFR Amplification
12. Epithelial Ovarian Cancer
13. Hepatocellular Carcinoma
14. Anaplastic Thyroid Cancer
15. Pancreas Cancer

Interventions

1. Drug: BCA101
2. Drug: Pembrolizumab

MeSH:Carcinoma Carcinoma, Squamous Cell Glioblastoma Triple Negative Breast Neoplasms Squamous Cell Carcinoma of Head and Neck Carcinoma, Ovarian Epithelial Pancreatic Neoplasms Chordoma Thyroid Carcinoma, Anaplastic Lung Neoplasms

HPO:Anaplastic thyroid carcinoma Carcinoma Chordoma Glioblastoma multiforme Neoplasm of the lung Neoplasm of the pancreas Squamous cell carcinoma

i Single agent BCA101 - patients with the following tumor types will be eligible: 1) Squamous Cell Lung Cancer (SqCLC) 2) Squamous Cell Carcinoma of the Head and Neck (HNSCC) 3) RAS wild-type microsatellite stable Colorectal Carcinoma (RAS WT MSS CRC) 4) Triple Negative Breast Cancer (TNBC) 5) Chordoma 6) Squamous Cell Carcinoma of the Anal Canal (SCCAC) 7) Uveal Melanoma 8) Glioblastoma (GBM) 9) Gastric Cancer 10) Any solid tumor with a KRAS G12D or G13D mutation 11) Any solid tumor with EGFR amplification 12) Epithelial Ovarian Cancer 13) Hepatocellular Carcinoma (HCC) 14) Anaplastic Thyroid Cancer (ATC) 15) Pancreatic Cancer 16) Other EGFR-driven advanced solid tumors (if there is compelling data or evidence to enroll a patient with a tumor type other than those listed in 1 - 15, the treating physician may discuss the patient with the Sponsor to determine eligibility). --- G12D ---

i Single agent BCA101 - patients with the following tumor types will be eligible: 1. PD-L1 negative, EGFR-amplified SqCLC 2. RAS WT MSS CRC 3. EGFR-amplified TNBC 4. Any solid tumor with a KRAS G12D or G13D mutation ii. --- G12D ---

TNBC - Triple-Negative Breast Cancer Head and Neck Squamous Cell Carcinoma Squamous Cell Carcinoma of Anal Canal Uveal Melanoma Glioblastoma Colorectal Cancer Chordoma Squamous Cell Carcinoma of the Lung KRAS G12D KRAS G13D EGFR Amplification Epithelial Ovarian Cancer Hepatocellular Carcinoma Anaplastic Thyroid Cancer Pancreas Cancer Carcinoma Carcinoma, Squamous Cell Glioblastoma Triple Negative Breast Neoplasms Squamous Cell Carcinoma of Head and Neck Carcinoma, Ovarian Epithelial Pancreatic Neoplasms Chordoma Thyroid Carcinoma, Anaplastic Lung Neoplasms This is a Phase 1/1b, open-label study, which consists of dose escalation parts (Part A) followed by expansion cohorts (Part B) for both single agent BCA101 and combination BCA101 plus pembrolizumab. --- G12D ---

Planned expansion cohorts for single agent BCA101 include 1) PD-L1 negative, EGFR-amplified Squamous Cell Lung Cancer (SqCLC); 2) RAS wild-type, microsatellite stable Colorectal Carcinoma (RAS wt, MSS CRC); 3) EGFR-amplified Triple Negative Breast Cancer; and 4) any solid tumor with either a KRAS G12D or G13D mutation. --- G12D ---

The purpose of this study is to determine if it is safe to add multiple immunotherapies to standard chemotherapy and radiation for treating pancreatic cancer tumors that cannot be completely removed by surgery. 1. GI-4000 Vaccination: The first involves a "vaccine," which is an injection (shot) that teaches your immune system to attack foreign invaders. The vaccine we will use is called "GI-4000" - a vaccine composed of yeast that is made to carry the same proteins (called "mutated Ras proteins") found in some pancreatic cancer cells. 2. Adoptive T-cell Transfer: The second type of immunotherapy in this study is called "adoptive T-cell transfer." This involves collecting a specific type of white blood cells from you (called "T-cells")and growing T-cells grown in a lab which may help the research participants' immune systems recover more quickly after chemotherapy, and possibly improved response to other immunotherapies. We hope that studying these agents together will teach us how to help the immune system fight pancreatic cancer.

NCT00837135

Conditions

1. Pancreatic Cancer

Interventions

1. Other: Screening
2. Biological: GI-4000 Vaccine
3. Biological: GI-4000 Vaccine + Activated T Cells
4. Biological: Surgical Evaluation after Vaccine #4

MeSH:Pancreatic Neoplasms

HPO:Neoplasm of the pancreas

1. Histologically-confirmed pancreatic adenocarcinoma that expresses one of the GI-4000-related k-ras oncoproteins (G12V, G12C, G12D, Q61L, or Q61R) 2. Locally advanced disease, (stages I-III, i.e no evidence of metastasis outside the pancreas and its regional lymph nodes). --- G12V --- --- G12C --- --- G12D ---

This study will determine the safety and tolerability and establish a preliminary recommended Phase 2 dose of V941(mRNA-5671/V941) as a monotherapy and in combination with pembrolizumab infusion.

NCT03948763

Conditions

1. Neoplasms
2. Carcinoma, Non-Small-Cell Lung
3. Pancreatic Neoplasms
4. Colorectal Neoplasms

Interventions

1. Biological: V941
2. Biological: Pembrolizumab

MeSH:Neoplasms Carcinoma, Non-Small-Cell Lung Colorectal Neoplasms Pancreatic Neoplasms

HPO:Neoplasm Neoplasm of the large intestine Neoplasm of the pancreas Non-small cell lung carcinoma

All - Has a histologically confirmed advanced or metastatic KRAS 4MUT+ (G12D, G12V, G13D or G12C) (4 prevalent KRAS mutant antigens in solid tumors) solid tumor identified by local laboratory testing, and who have received, or been intolerant to, or ineligible for all treatment known to confer clinical benefit. --- G12D ---

This study is a multi-center, open-label, dose escalation study of RLY-1971 in subjects with advanced or metastatic solid tumors.

NCT04252339

Conditions

1. Solid Tumor, Unspecified, Adult

Interventions

1. Drug: RLY-1971

MeSH:Neoplasms

HPO:Neoplasm

Male and female subjects of child-bearing potential are willing to use medically acceptable methods of birth control from the screening visit through 30 days after the last dose of study medication Exclusion Criteria: 1. Subjects with documented history of tumor mutations that may not be amenable to treatment with RLY-1971, including 1. KRAS mutations: G12D, G12V, G13X, and Q61X 2. BRAF V600E mutation 3. MEK mutations 2. Subjects with prior antineoplastic therapy within 3 weeks of Study Day 1, or 5 half-lives, whichever is shorter 3. Subjects with prior palliative radiotherapy within 1 week of Study Day 1 4. Subjects who have had major surgery or trauma, or incomplete recovery from surgery or trauma, within 4 weeks of Study Day 1 5. Subjects with known central nervous system (CNS) primary tumor, uncontrolled CNS metastases, or carcinomatous meningitis. --- G12D ---

The purpose of this study is to test the drug Bortezomib to see how well it works. The investigators want to find out what effects, good or bad, it has on patients with a limited smoking history or who have a specific mutation associated with their lung cancer.

NCT01833143

Conditions

1. Non-Small Cell Lung Cancer

Interventions

1. Drug: Bortezomib
2. Drug: Acyclovir

MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung

HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase 2 Trial of Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never Smokers or Those With KRAS G12D. --- G12D ---

Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never Smokers or Those With KRAS G12D The purpose of this study is to test the drug Bortezomib to see how well it works. --- G12D ---

Inclusion Criteria: - Pathologic or cytologic evidence of non-small cell lung cancer (NSCLC) - Documented KRAS mutation - History of smoking < 100 cigarettes (never-smoker) OR patient with a KRAS G12D mutation regardless of smoking history - Clinical stage IIIB/IV or recurrent/medically inoperable NSCLC - Age ≥ 18 years - Three (3) weeks since last chemotherapy, and three (3) weeks since prior radiation therapy and recovered from treatment - Karnofsky performance status ≥ 70% - Adequate hematologic, and/or hepatic function WBC ≥ 3,000/ul or absolute neutrophil count ≥ 1,000/ul Hemoglobin ≥ 9.0 g/dl Platelet count ≥ 100,000/ul AST ≤ 2.0 X ULN (upper limit of normal) - Total bilirubin ≤1.5 x ULN Measurable indicator lesions by RECIST v1.1 criteria. --- G12D ---

- No active concurrent malignancy, with the exception of in-situ malignancy completely resected basal cell carcinoma or squamous cell carcinomas of the skin low-risk prostate cancer after curative therapy - Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial Inclusion Criteria: - Pathologic or cytologic evidence of non-small cell lung cancer (NSCLC) - Documented KRAS mutation - History of smoking < 100 cigarettes (never-smoker) OR patient with a KRAS G12D mutation regardless of smoking history - Clinical stage IIIB/IV or recurrent/medically inoperable NSCLC - Age ≥ 18 years - Three (3) weeks since last chemotherapy, and three (3) weeks since prior radiation therapy and recovered from treatment - Karnofsky performance status ≥ 70% - Adequate hematologic, and/or hepatic function WBC ≥ 3,000/ul or absolute neutrophil count ≥ 1,000/ul Hemoglobin ≥ 9.0 g/dl Platelet count ≥ 100,000/ul AST ≤ 2.0 X ULN (upper limit of normal) - Total bilirubin ≤1.5 x ULN Measurable indicator lesions by RECIST v1.1 criteria. --- G12D ---

This research study is designed to evaluate the effects of a dendritic cell (kind of white blood cell) vaccine for pancreatic cancer.

NCT03592888

Conditions

1. Pancreatic Ductal Adenocarcinoma

Interventions

1. Drug: mDC3/8-KRAS Vaccine

MeSH:Adenocarcinoma

Inclusion Criteria: - Pathologically-confirmed KRAS(G12D-), KRAS(G12V-), KRAS(G12R-) or KRAS(G12C-mutated) pancreatic ductal adenocarcinoma who are at high risk of relapse and have no evidence of disease. --- G12D ---

This clinical trial will evaluate the safety and activity of mutant KRAS G12V-specific TCR transduced T cell therapy for advanced pancreatic cancer patients who express the KRAS G12V mutation and HLA-A*11:01 allele. The theoretical basis of this study is that mutant KRAS antigen-specific TCR transduced autologous Tcells will target and kill HLA-matched mutant KRAS cancer cells but not normal cells.

NCT04146298

Conditions

1. Pancreatic Cancer
2. Pancreatic Neoplasms
3. Pancreatic Ductal Adenocarcinoma
4. Advanced Cancer

Interventions

1. Drug: Cyclophosphamide
2. Drug: Fludarabine
3. Biological: Mutant KRAS G12V-specific TCR transduced autologous T cells
4. Drug: Anti-PD-1 monoclonal antibody

MeSH:Pancreatic Neoplasms

HPO:Neoplasm of the pancreas

For example, TCRs that target mutant KRAS G12D peptides presented by HLA-C*08:02, and a TCR that targets a KRAS G12V peptide presented by HLA-A*11:01 have been identified. --- G12D ---

Mutant KRAS-reactive T cells appear capable of inducing tumor regression as highlighted in a patient with metastatic colorectal cancer who experienced regression of metastatic tumors after infusion of HLA-C*08:02-restricted KRAS-G12D reactive tumor-infiltrating lymphocytes (TIL). --- G12D ---

Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-70 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: - Get 2 chemotherapy medicines by IV over 5 days. - Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. - Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.

NCT03745326

Conditions

1. Gastrointestinal Cancer
2. Pancreatic Cancer
3. Gastric Cancer
4. Colon Cancer
5. Rectal Cancer

Interventions

1. Drug: Cyclophosphamide
2. Drug: Fludarabine
3. Drug: Aldesleukin
4. Biological: anti-KRAS G12D mTCR PBL

MeSH:Gastrointestinal Neoplasms

HPO:Malignant gastrointestinal tract tumors Neoplasm of the gastrointestinal tract

A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients. --- G12D ---

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. --- G12D ---

It is called gene transfer using anti-KRAS G12D mTCR cells. --- G12D ---

Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. --- G12D ---

-INCLUSION CRITIERIA: 1. Measurable (per RECIST v1.1 criteria), metastatic, or unresectable malignancy expressing G12D mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on resected tissue. --- G12D ---

Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D ---

Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D --- --- G12D ---

Gastrointestinal Cancer Pancreatic Cancer Gastric Cancer Colon Cancer Rectal Cancer Gastrointestinal Neoplasms Background: - We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12D-mutated variant of KRAS (and other RAS family genes) expressed by many human cancers and constructed a single retroviral vector that contains alpha and beta chains that confer recognition of this antigen when transduced into PBL. --- G12D ---

Objectives: -Primary objectives: - Phase I: Determine the safety of administering PBL transduced with anti-KRAS G12D mTCR in concert with preparative lymphodepletion and high-dose interleukin-2 (IL-2; aldesleukin). --- G12D ---

- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D ---

- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D --- --- G12D ---

Eligibility: - Patients must be/have: - Age greater than or equal to 18 years and less than or eqaul to 70 years - HLA-A*11:01 positive - Metastatic or unresectable RAS G12D-expressing cancer which has progressed after standard therapy (if available). --- G12D ---

Design: - This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. - PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D ---

Design: - This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. - PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D --- --- G12D ---

- Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12D mTCR. --- G12D ---

- On Day 0, patients will receive PBL transduced with the anti-KRAS G12D mTCR and will then begin high-dose aldesleukin. --- G12D ---

- The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. --- G12D ---

- The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. --- G12D --- --- G12D ---

The purpose of this study is to determine whether carboplatin-paclitaxel-bevacizumab results in a prolonged progression free survival compared to cisplatin-pemetrexed as first line treatment in patients with KRAS mutated non-small cell lung cancer.

NCT02743923

Conditions

1. Carcinoma, Non-Small Cell Lung

Interventions

1. Drug: carboplatin
2. Drug: paclitaxel
3. Drug: Bevacizumab
4. Drug: Pemetrexed
5. Drug: cisplatin

MeSH:Carcinoma, Non-Small-Cell Lung

HPO:Non-small cell lung carcinoma

The two most common KRAS types are G12C in about 40% of cases, G12V in 18% and G12D in 15% of cases. --- G12C --- --- G12V --- --- G12D ---

The purpose of this study is to see if TAS0612 is safe in participants with advanced or metastatic solid tumor cancer.

NCT04586270

Conditions

1. Advanced or Metastatic Solid Tumors

Interventions

1. Drug: TAS0612

MeSH:Neoplasms

HPO:Neoplasm

The levels/changes of the phospho-proteins will be assessed and reported for target modulation.. Inclusion Criteria: - Dose Escalation: have evidence of a solid tumor that is locally advanced and/or metastatic (excluding primary brain tumor) - Dose Expansion: have evidence of a solid tumor as outlined below that is locally advanced and/or metastatic (excluding primary brain tumor) - Cohort A: Human epidermal growth factor negative (HER2 negative) Breast Cancer with an NF1 mutation - Cohort B: Hormone receptor positive (HR+)/HER2 negative breast cancer after progression on endocrine therapy and a CDK4/6 inhibitor - Cohort C: PTEN loss or mutations - Cohort D: KRAS G12C mutation - Cohort E: KRAS G12D mutation - Have adequate organ function - Amenable to biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Exclusion Criteria: - Participating in medical research not compatible with this study - Have not discontinued or recovered from previous treatments for cancer - Have a significant cardiac condition - Have untreated brain metastases - Have a primary brain tumor - Have a serious concomitant disorder - Unable to swallow or digest pills - Poorly controlled diabetes - Concomitant medications or substances that are strong inhibitors/inducers of CYP3A.Study Inclusion Criteria: - Dose Escalation: have evidence of a solid tumor that is locally advanced and/or metastatic (excluding primary brain tumor) - Dose Expansion: have evidence of a solid tumor as outlined below that is locally advanced and/or metastatic (excluding primary brain tumor) - Cohort A: Human epidermal growth factor negative (HER2 negative) Breast Cancer with an NF1 mutation - Cohort B: Hormone receptor positive (HR+)/HER2 negative breast cancer after progression on endocrine therapy and a CDK4/6 inhibitor - Cohort C: PTEN loss or mutations - Cohort D: KRAS G12C mutation - Cohort E: KRAS G12D mutation - Have adequate organ function - Amenable to biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Exclusion Criteria: - Participating in medical research not compatible with this study - Have not discontinued or recovered from previous treatments for cancer - Have a significant cardiac condition - Have untreated brain metastases - Have a primary brain tumor - Have a serious concomitant disorder - Unable to swallow or digest pills - Poorly controlled diabetes - Concomitant medications or substances that are strong inhibitors/inducers of CYP3A.Study Advanced or Metastatic Solid Tumors Neoplasms null --- G12C --- --- G12D ---

The levels/changes of the phospho-proteins will be assessed and reported for target modulation.. Inclusion Criteria: - Dose Escalation: have evidence of a solid tumor that is locally advanced and/or metastatic (excluding primary brain tumor) - Dose Expansion: have evidence of a solid tumor as outlined below that is locally advanced and/or metastatic (excluding primary brain tumor) - Cohort A: Human epidermal growth factor negative (HER2 negative) Breast Cancer with an NF1 mutation - Cohort B: Hormone receptor positive (HR+)/HER2 negative breast cancer after progression on endocrine therapy and a CDK4/6 inhibitor - Cohort C: PTEN loss or mutations - Cohort D: KRAS G12C mutation - Cohort E: KRAS G12D mutation - Have adequate organ function - Amenable to biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Exclusion Criteria: - Participating in medical research not compatible with this study - Have not discontinued or recovered from previous treatments for cancer - Have a significant cardiac condition - Have untreated brain metastases - Have a primary brain tumor - Have a serious concomitant disorder - Unable to swallow or digest pills - Poorly controlled diabetes - Concomitant medications or substances that are strong inhibitors/inducers of CYP3A.Study Inclusion Criteria: - Dose Escalation: have evidence of a solid tumor that is locally advanced and/or metastatic (excluding primary brain tumor) - Dose Expansion: have evidence of a solid tumor as outlined below that is locally advanced and/or metastatic (excluding primary brain tumor) - Cohort A: Human epidermal growth factor negative (HER2 negative) Breast Cancer with an NF1 mutation - Cohort B: Hormone receptor positive (HR+)/HER2 negative breast cancer after progression on endocrine therapy and a CDK4/6 inhibitor - Cohort C: PTEN loss or mutations - Cohort D: KRAS G12C mutation - Cohort E: KRAS G12D mutation - Have adequate organ function - Amenable to biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Exclusion Criteria: - Participating in medical research not compatible with this study - Have not discontinued or recovered from previous treatments for cancer - Have a significant cardiac condition - Have untreated brain metastases - Have a primary brain tumor - Have a serious concomitant disorder - Unable to swallow or digest pills - Poorly controlled diabetes - Concomitant medications or substances that are strong inhibitors/inducers of CYP3A.Study Advanced or Metastatic Solid Tumors Neoplasms null --- G12C --- --- G12D --- --- G12C --- --- G12D ---