• Patients will be eligible for study participation only if they meet ALL the inclusion criteria applicable to their diagnosis.

• Understand and sign the informed consent form (ICF) and be willing to comply with all study procedures before any study specific procedures are conducted.

• ≥18 years old at the time of signing the informed consent.

• Diagnosed with unresectable, locally advanced, or metastatic solid tumors including ER+ HER2- breast cancer (Cohort 1) or melanoma (Cohort 2)

• a.Underlying malignant disease must be histologically or cytologically documented b.For breast cancer patients: locally advanced or metastatic breast cancer with one or more actionable PIK3CA/AKT1/PTEN-alterations following progression on at least 2 endocrine-based regimens in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. Patients who are candidates to start therapy with capivasertib are eligible for enrollment. Patients previously treated with PIK3CA inhibitors will be allowed into the study. Premenopausal patients with ER+ HER2-breast cancer may be enrolled and should be maintained on an agent for ovarian suppression (i.e., luteinizing hormone-releasing hormone \[LHRH\] agonist) as part of SOC.

• c.For melanoma patients: patients with unresectable metastatic cutaneous melanoma that progressed on any prior immune checkpoint inhibitor and, if BRAF600 mutant positive, a BRAF or mitogen-activated protein kinase (MEK) inhibitor or both as shown below: i.Patient have to have resolution of all immune checkpoint inhibitor-related adverse events to Grade 0-1 and prednisone ≤10 mg/day for at least 2 weeks. Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy.

• ii.Patients must have progressed or shown intolerance to any prior immune checkpoint inhibitors.

• iii.Patients with BRAF gene mutant melanoma must have had a prior treatment regimen (progressed or shown intolerance) that included vemurafenib, dabrafenib, or an approved BRAF gene and or MEK protein inhibitor. However, patients who may continue to be candidates for second line immune check point inhibitors can be enrolled prior to initiation for BRAF gene or MEK inhibitors.

• iv.Patients with incurable malignancies may be enrolled regardless of the number of prior treatment lines, as long as in the opinion of the Investigator, the patient would be unlikely to tolerate or derive clinically meaningful benefit from other available treatment options (FDA Guidance for Industry: Cancer Clinical Trial Eligibility Criteria: Available Therapy in Non-Curative Settings. July 2022).

• d.Has evaluable or measurable disease by tumor Response Evaluable Criteria in Solid Tumors version 1.1 (RECIST 1.1) at the time of enrollment. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

• e.Patients with brain previously treated stable brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.

• Patients must be willing to undergo a fresh tumor biopsy at Screening and during treatment if safe and clinically feasible. An archival sample is allowed if obtained within 1 year prior to the first dose of study drug. However, lack of tumor biopsy by itself will not preclude patients from enrollment.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening or Day 1.

• Life expectancy of at least 12 weeks.

• Adequate organ function defined as:

• a.Absolute neutrophil count (ANC) ≥1.5×109/L without granulocyte colony-stimulating factor (G-CSF) support within 7 days preceding the laboratory assessment b.Platelet ≥100×109/L, without transfusion within 7 days preceding the laboratory assessment c.Hemoglobin ≥9 g/dL, without transfusion support within 7 days preceding the laboratory assessment d.Activated partial thromboplastin time/partial thromboplastin time (aPTT/PTT) ≤1.5×ULN e.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN (if liver metastases are present, then ≤5×ULN is allowed) f.Total serum bilirubin ≤1.5×ULN, except for patients with known Gilbert's Syndrome in whom ≤3×ULN is permitted. Confirmation of Gilbert's diagnosis requires elevated unconjugated (indirect) bilirubin values; normal complete blood count in previous 12 months, blood smear, and reticulocyte count; normal aminotransferases and alkaline phosphatase in previous 12 months g.The patient is clinically euthyroid (whether treated or untreated) h.Renal: Serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL/min/1.73 m2 for patients with serum creatinine levels \>1.5×ULN i.Any Grade 3 or higher laboratory abnormalities should be discussed and approved by the Sponsor Medical Monitor or designee prior to enrollment (even if not considered clinically significant)

• Fully recovered from acute toxic effects of prior anti-neoplastic therapies. The following minimum periods from treatment apply:

∙ Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).

‣ Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g., Neulasta) or 7 days for short-acting growth factor.

‣ Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur.

• The duration of this interval must be discussed with the Sponsor Medical Monitor or designee.

• d.Monoclonal antibodies: \>21 days must have elapsed from the infusion of last dose of antibody and toxicity related to antibody therapy must be recovered to Grade ≤1.

• e.Radiation therapy: Patients must have had their last fraction of craniospinal or focal irradiation a minimum of 8-12 weeks prior to enrollment.

• f.Stem cell transplant: Patients must be ≥3 months since autologous stem cell transplant. Patients who received allogenic stem cell transplant or solid organ transplant are not eligible for study.

• g.For combination with pembrolizumab cohort: Patients with Grade ≤2 neuropathy may be eligible, as may patients with endocrine-related Grade ≤2 AEs requiring treatment or hormone replacement.

• Active secondary malignancies will not be allowed, with the exception of:

• a.Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b.Adequately treated Stage 1 cancer from which the patient is currently in remission and has been in remission for ≥2 years c.Low-risk prostate cancer with Gleason score \<7 and prostate-specific antigen \<10 ng/mL d.Any other cancer from which the patient has been disease-free for ≥3 years

⁃ Patient compliance and geographic proximity (as determined by the Investigator) to allow adequate follow-up.

⁃ Both male and female patients must be willing to consent to using highly effective contraception (refer to Section 9.1.10) prior to study entry, while on treatment, and at least 3 months thereafter.

⁃ Able to take oral medications.