Brief Title: Study of ADCT-301 in Patients With Selected Advanced Solid Tumors

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Part 1 Monotherapy: Number of Patients Who Experience a Treatment-emergent Adverse Event (TEAE)

Primary Outcome 1 - Timeframe: Up to 3 years

Primary Outcome 2 - Measure: Part 1 Combination Therapy: Number of Patients Who Experience a Treatment-emergent Adverse Event (TEAE)

Primary Outcome 2 - Timeframe: Up to 3 years

Primary Outcome 3 - Measure: Part 2 Combination Therapy: Number of Patients Who Experience a Treatment-emergent Adverse Event (TEAE)

Primary Outcome 3 - Timeframe: Up to 3 years

Primary Outcome 4 - Measure: Part 1 Monotherapy: Number of Patients Who Experience a Treatment-emergent Adverse Event (TEAE) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above

Primary Outcome 4 - Timeframe: Up to 3 years

Primary Outcome 5 - Measure: Part 1 Combination Therapy: Number of Patients Who Experience a Treatment-emergent Adverse Event (TEAE) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above

Primary Outcome 5 - Timeframe: Up to 3 years

Primary Outcome 6 - Measure: Part 2 Combination Therapy: Number of Patients Who Experience a Treatment-emergent Adverse Event (TEAE) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above

Primary Outcome 6 - Timeframe: Up to 3 years

Primary Outcome 7 - Measure: Part 1 Monotherapy: Number of Patients Who Experience a Serious Adverse Event (SAE)

Primary Outcome 7 - Timeframe: Up to 3 years

Primary Outcome 8 - Measure: Part 1 Combination Therapy: Number of Patients Who Experience a Serious Adverse Event (SAE)

Primary Outcome 8 - Timeframe: Up to 3 years

Primary Outcome 9 - Measure: Part 2 Combination Therapy: Number of Patients Who Experience a Serious Adverse Event (SAE)

Primary Outcome 9 - Timeframe: Up to 3 years

Primary Outcome 10 - Measure: Part 1 Monotherapy: Number of Patients with a Serious Adverse Event (SAE) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above

Primary Outcome 10 - Timeframe: Up to 3 years

Primary Outcome 11 - Measure: Part 1 Combination Therapy: Number of Patients with a Serious Adverse Event (SAE) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above

Primary Outcome 11 - Timeframe: Up to 3 years

Primary Outcome 12 - Measure: Part 2 Combination Therapy: Number of Patients with a Serious Adverse Event (SAE) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Above

Primary Outcome 12 - Timeframe: Up to 3 years

Primary Outcome 13 - Measure: Part 1 Monotherapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Laboratory Values

Primary Outcome 13 - Timeframe: Baseline to up to 3 years

Primary Outcome 14 - Measure: Part 1 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Laboratory Values

Primary Outcome 14 - Timeframe: Baseline to up to 3 years

Primary Outcome 15 - Measure: Part 2 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Laboratory Values

Primary Outcome 15 - Timeframe: Baseline to up to 3 years

Primary Outcome 16 - Measure: Part 1 Monotherapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Vital Signs

Primary Outcome 16 - Timeframe: Baseline to up to 3 years

Primary Outcome 17 - Measure: Part 1 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Vital Signs

Primary Outcome 17 - Timeframe: Baseline to up to 3 years

Primary Outcome 18 - Measure: Part 2 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Vital Signs

Primary Outcome 18 - Timeframe: Baseline to up to 3 years

Primary Outcome 19 - Measure: Part 1 Monotherapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

Primary Outcome 19 - Timeframe: Baseline to up to 3 years

Primary Outcome 20 - Measure: Part 1 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

Primary Outcome 20 - Timeframe: Baseline to up to 3 years

Primary Outcome 21 - Measure: Part 2 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

Primary Outcome 21 - Timeframe: Baseline to up to 3 years

Primary Outcome 22 - Measure: Part 1 Monotherapy: Number of Patients who Experience a Clinically Significant Change from Baseline in 12-lead Electrocardiograms (ECGs)

Primary Outcome 22 - Timeframe: Baseline to up to 3 years

Primary Outcome 23 - Measure: Part 1 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in 12-lead Electrocardiograms (ECGs)

Primary Outcome 23 - Timeframe: Baseline to up to 3 years

Primary Outcome 24 - Measure: Part 2 Combination Therapy: Number of Patients who Experience a Clinically Significant Change from Baseline in 12-lead Electrocardiograms (ECGs)

Primary Outcome 24 - Timeframe: Baseline to up to 3 years

Primary Outcome 25 - Measure: Part 1 Monotherapy: Number of Patients who Experience a Dose Interruption

Primary Outcome 25 - Timeframe: Up to 3 years

Primary Outcome 26 - Measure: Part 1 Combination Therapy: Number of Patients who Experience a Dose Interruption

Primary Outcome 26 - Timeframe: Up to 3 years

Primary Outcome 27 - Measure: Part 2 Combination Therapy: Number of Patients who Experience a Dose Interruption

Primary Outcome 27 - Timeframe: Up to 3 years

Primary Outcome 28 - Measure: Part 1 Monotherapy: Number of Patients who Experience a Dose Reduction

Primary Outcome 28 - Timeframe: Up to 3 years

Primary Outcome 29 - Measure: Part 1 Combination Therapy: Number of Patients who Experience a Dose Reduction

Primary Outcome 29 - Timeframe: Up to 3 years

Primary Outcome 30 - Measure: Part 2 Combination Therapy: Number of Patients who Experience a Dose Reduction

Primary Outcome 30 - Timeframe: Up to 3 years

Primary Outcome 31 - Measure: Part 1 Monotherapy: Number of Patients who Experience a Dose Limiting Toxicity (DLT)

Primary Outcome 31 - Timeframe: Day 1 to Day 21

Primary Outcome 32 - Measure: Part 1 Combination Therapy: Number of Patients who Experience a Dose Limiting Toxicity (DLT)

Primary Outcome 32 - Timeframe: Day 1 to Day 21

CONDITION

• Advanced Solid Tumors With Literature Evidence of CD25(+) Treg Content
• Head and Neck Cancer Squamous Cell Carcinoma
• Non-small Cell Lung Cancer
• Gastric Cancer
• Esophageal Cancer
• Pancreas Cancer
• Bladder Cancer
• Renal Cell Carcinoma
• Melanoma
• Triple-negative Breast Cancer
• Ovarian Cancer
• Colo-rectal Cancer
• Fallopian Tube Cancer

ELIGIBILITY

Inclusion Criteria:
Written informed consent must be obtained prior to any procedures.

- Male or female patient aged 18 years or older.
Pathologic diagnosis of solid tumor malignancy that is locally advanced or metastatic at time of Screening:
Part 1 Dose escalation camidanlumab tesirine as monotherapy:
Selected advanced solid tumors: colorectal, head and neck, NSCLC, gastric and esophageal cancers, pancreas, bladder, renal cell carcinoma, melanoma, TNBC, and ovarian/fallopian tube cancers
Part 1 Dose-escalation camidanlumab tesirine in combination with pembrolizumab:
Selected advanced solid tumors: colorectal cancer, gastric-esophageal cancer, ovarian /fallopian tube cancer, pancreatic cancer, non-small cell lung cancer, and melanoma.
Note: For colorectal cancer, gastric-esophageal cancer, ovarian/fallopian tube cancer, pancreatic cancers mismatch repair (MMR) / microsatellite stability (MSS) / microsatellite instability (MSI) status is mandatory. If MMR/MSS/MSI status is not available at signature of the informed consent, the test should be performed before Cycle 1 Day 1 (C1D1).
Part 2 Dose expansion camidanlumab tesirine in combination with pembrolizumab:
Group 1: One of the indications identified in Part 1, for which at least 1 response (PR or CR) was seen.

- Group 2: Patients with advanced solid tumors and MSI-H/dMMR status, who have received a prior regimen containing PD-1/PD-L1 inhibitors, for which the best response was CR, PR, or SD ≥4 months, and then progressed while under treatment with the PD-1/PD-L1 inhibitor-based regimen.
Note: A maximum of 4 patients with the same indication will be allowed in this basket group.
Patients who are refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.

- Patients with advanced/metastatic cancer, with measurable disease as determined by RECIST v1.1 or immune-related Response Criteria (irRC)/ immune-related Response Evaluation Criteria In Solid Tumors (irRECIST)/ immune-related Response Evaluation Criteria In Solid Tumors (iRECIST)/ immune-modified Response Evaluation Criteria in Solid Tumors (imRECIST) as per Investigator discretion.
A) For camidanlumab tesirine as monotherapy: Patient must have a site of disease amenable to biopsy and be willing to undergo fresh biopsy procedures (minimum 3 passes each) prior to first dose, according to the treating institution's guidelines.
B) Patients included in the paired-biopsy cohort must in addition be willing to undergo fresh biopsy procedures (minimum 3 passes each) after receiving at least 1 dose of study drug.
C) For camidanlumab tesirine in combination with pembrolizumab: Patient must either have a site of disease amenable to biopsy and must provide fresh tumor biopsy prior to C1D1, or have sufficient available archival tumor tissue (biopsied after their last disease progression, and in the situation where the patient has received no additional anti-cancer therapy between their progression and C1D1). Patients must also be willing to undergo fresh biopsy procedures (minimum 3 passes each) after receiving at least 1 dose of study treatment, according to the treating institution's guidelines.
ECOG performance status 0-1.

- Patient with life expectancy ≥ 3 months as per Investigator assessment.
Adequate organ function as defined by screening laboratory values within the following parameters:
Absolute neutrophil count (ANC) ≥ 1.5 × 10^3/μL (off growth factors at least 72 hours).

- Platelet count ≥100 × 10^3/μL without transfusion in the past 10 days.

- Hemoglobin ≥9 g/dL (5.6 mmol/L) (prior transfusion allowed).

- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma glutamyl transferase (GGT) ≤2.5 × the upper limit of normal (ULN) if there is no liver involvement; ALT or AST ≤5 × ULN if there is liver involvement.

- Total bilirubin ≤1.5 × ULN (patients with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN with direct bilirubin ≤1.5 × ULN).

- Blood creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min by the Cockcroft-Gault equation.

- Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to start of study drug for women of childbearing potential (WOCBP).

- Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 9.5 months after the last dose of camidanlumab tesirine or 4 months after last dose of pembrolizumab, whichever is the latest. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of giving informed consent until at least 6.5 months after the patient receives his last dose of camidanlumab tesirine or 4 months after last dose of pembrolizumab, whichever is the latest.
Exclusion Criteria:
Participation in another investigational interventional study.

- Prior therapy with a CD25 (IL-2R) antibody.

- Known history of ≥Grade 3 hypersensitivity to a therapeutic antibody.

- Patients with prior solid organ or allogeneic bone marrow transplant.

- History of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjögren's syndrome, autoimmune vasculitis [e.g., Wegener's granulomatosis]) (patients with vitiligo, type 1 diabetes mellitus, residual hypothyroidism, hypophysitis due to autoimmune condition only requiring hormone replacement may be enrolled).

- History of neuropathy considered of autoimmune origin (e.g., polyradiculopathy including Guillain-Barré syndrome and myasthenia gravis) or other central nervous system (CNS) autoimmune disease (e.g., poliomyelitis, multiple sclerosis).
History of recent infection (within 4 weeks of C1D1) caused by a pathogen known to be associated with GBS, for example: herpes simplex virus 1/2 (HSV1, HSV2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), measles, Influenza A, Zika virus, Chikungunya virus, mycoplasma pneumonia, Campylobacter jejuni, enterovirus D68, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Note: An influenza test and a pathogen-directed SARS-CoV-2 test (such as polymerase chain reaction [PCR]) are mandatory and must be negative before initiating study treatment (tests to be performed 3 days or less prior to dosing on C1D1; an additional 2 days are allowed in the event of logistical issues for receiving the results on time).
Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus, hepatitis B virus (HBV), or hepatitis C virus (HCV). Note: Testing is not mandatory to be eligible but should be considered in patients with high risk for these infections; testing is mandatory if status is unknown.

- History of Stevens-Johnson syndrome or toxic epidermal necrolysis.

- Failure to recover to ≤Grade 1 (Common Terminology Criteria for Adverse Events version 4.0 [CTCAE version 4.0]) from acute nonhematologic toxicity (to ≤Grade 2 for neuropathy or alopecia), due to previous therapy, prior to screening.

- Symptomatic CNS metastases or evidence of leptomeningeal disease (brain MRI or previously documented cerebrospinal fluid [CSF] cytology). Previously treated asymptomatic CNS metastases are permitted provided that the last treatment (systemic anticancer therapy and/or local radiotherapy) was completed ≥4 weeks prior to Day 1 except usage of low dose of steroids on a taper (i.e., up to 10 mg prednisone or equivalent on Day 1 and consecutive days is permissible if being tapered down). Patients with discrete dural metastases are eligible.

- Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath).

- Active diarrhea CTCAE Grade 2 or a medical condition associated with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease).

- Active infection requiring systemic antibiotic therapy.

- Active bleeding diathesis or significant anticoagulation (international normalized ratio [INR] ≥2.0).

- Breastfeeding or pregnant.

- Significant medical comorbidities, including uncontrolled hypertension (blood pressure [BP] ≥160 mmHg systolic and/or ≥110 mmHg diastolic repeatedly with or without anti hypertensive medication), unstable angina, congestive heart failure (greater than New York Heart Association class II), electrocardiographic evidence of acute ischemia, coronary angioplasty or myocardial infarction within 6 months prior to screening, severe uncontrolled atrial or ventricular cardiac arrhythmia, poorly controlled diabetes, active ulceration of the upper gastrointestinal (GI) tract or GI bleeding, or severe chronic pulmonary disease.

- Major surgery, radiotherapy, chemotherapy or other anti-neoplastic therapy within 14 days prior to start of study drug (C1D1), except shorter if approved by the Sponsor. For cytotoxic agents that have major delayed toxicity, e.g., mitomycin C and nitrosoureas, 4 weeks is indicated as washout period. For patients receiving systemic anticancer immunotherapies (as opposed to intralesional) that lead to activation of Teffs and/or increase the Teff/Treg ratio, such as anti-PD-1 antibodies, 4 weeks are indicated as the washout period.

- Use of any other experimental medication within 14 days prior to start of study drug (C1D1).
Patients requiring concomitant immunosuppressive agents or chronic treatment with corticosteroids except:
replacement dose steroids in the setting of adrenal insufficiency

- topical, inhaled, nasal, and ophthalmic steroids are allowed.

- Planned live vaccine within 30 days prior to the first dose of study treatment and during study treatment.

- Congenital long QT syndrome, or a corrected QTcF interval of ≥ 480 ms, at screening (unless secondary to pacemaker or bundle branch block).

- Active second primary malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's medical monitor and Investigator agree and document should not be exclusionary.

- Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the patient inappropriate for study participation or put the patient at risk.

- For patients treated with camidanlumab tesirine in combination with pembrolizumab: patients intolerant to checkpoint-inhibitor or with a history of the following ≥ Grade 3 immune-related adverse events: hepatitis, renal, ocular, neurologic, cardiovascular, rheumatologic, and hematologic.

- For patient treated with camidanlumab tesirine in combination with pembrolizumab: patients with a history of non-infectious pneumonitis related to prior systemic treatment and that require treatment with steroids within the last 6 months prior to enrollment.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: N/A

Role: N/A

Affiliation: N/A

Overall Contact

Name: N/A

Phone: 954-903-7994

Email: clinical.trials@adctherapeutics.com

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