Phase II Trial of Puxitatug Samrotecan (AZD8205) in Advanced, Recurrent or Metastatic (R/M) Aggressive Adenoid Cystic Carcinoma Subtype I (ACC-I)

Phase II open label study designed to evaluate the efficacy and safety of P-Sam in patients with aggressive, solid, NOTCH mutant or p63 low (B7-H4 high) R/M ACC-I patients.

Inclusion Criteria: 1. Patients ≥18 years with histology-proven advanced, or R/M ACC. 2. Evidence of locally advanced disease not amenable to curative intent surgery or radiotherapy, or recurrent/metastatic disease 3. ACC-I subtype defined by at least one of the following: a. Presence of an activating NOTCH mutation per in-house or any CLIA-certified or commercially available next-generation sequencing assay b. Solid histology (any amount of solid component) and clinical course characterized by \< 3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with extra-pulmonary metastasis c. Negative TP63 tumor expression by IHC (\ 470 msec 9. Any factors that increase the risk of corrected QT (interval) (QTc) prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. 10. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study intervention or during the scheduled ECG assessments (see \\>). 8\) Active CNS disease (patients with asymptomatic or treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks prior to start of study treatment are not considered active) 9) Uncontrolled intercurrent illness within the last 12 months of start of study treatment, including but not limited to serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent. 10\) Has substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator. 11\) Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live attenuated vaccine whilst receiving study intervention and up to 30 days after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the Investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines. Note: If a COVID-19 vaccine is administered it should be done \> 72 hours prior to study intervention initiation. 12\) For women only - currently pregnant (confirmed with positive pregnancy test), lactating, breastfeeding, or intend to become pregnant during the study. 13\) Red blood cell transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening. 14\) Current participation in another interventional clinical study 15) History of previous malignancy other than malignancy treated with curative intent and low risk of recurrence. Patients with the following diagnoses represents an exception and may enroll if ≥ 2 years with no evidence of active disease before the first dose of the study drug or if treatment is not indicated: a. Non-melanoma skin cancers with no current evidence of disease b. Melanoma in situ with no current evidence of disease c. Treated or localized, low-risk, cancer of the prostate with prostate-specific antigen of \