Studies

Full description

This is an observational, non-interventional, multicenter study. The study will be performed within the Dutch GIST consortium (NKI-AvL, Erasmus MC, Radboud UMC, LUMC and UMCG). Patients diagnosed with GIST with a KIT exon 11 mutations that can be detected by our ddPCR assay are eligible. In this way we will study a homogenous patient population with GIST that (usually) responds very well to initial TKI treatment. Therefore, the KIT mutation status must be known. Patients can enter the study at any time point of their disease trajectory. Patients included in GALLOP-11 will have follow-up as described in the European Society of Medical Oncology and Dutch guidelines but with blood draws for ctDNA assessment at similar time points.

The primary objective is the negative predictive value (NPV) of the ddPCR assay result in relation to the results of the CT-scan and/or MRI scan (according to RECIST 1.1) at the same time point. Concordance of these results will be determined, from which the negative predictive value (NPV) of our ddPCR assay will be calculated. This is considered the most important value, as the most harmful scenario would be to miss progressive disease because not seen on ctDNA while it could have been seen on CT (and/or MRI). That would mean that ctDNA analysis is not reliable enough to replace CT-scan (and/or MRI) follow-up in the future.

To determine the negative predictive value, at least 250 patients need to have an evaluable follow-up strategy. To pursue a solid follow-up period within an achievable timeline, patients with at least four ctDNA measurements, accompanied by a CT-scan (and/or MRI scan), will be considered evaluable for the NPV analysis. Patients who have progression within four scans are always evaluable, since a positive outcome outweighs negative outcomes because it is known that ctDNA should have had measured change once it is seen on CT-scans (and/or MRI scans).

Inclusion criteria

1. Patients with GIST with a biopsy confirmed primary KIT exon 11 mutation covered by our KIT exon 11 ddPCR assay (mutation/deletion within target sequence of c.1665_1736);
2. Patients with an indication for at least 4 CT-scans concomitant with regular laboratory examination in a neoadjuvant, adjuvant and/or palliative care trajectory within the time frame of the study;
3. Age ≥18 years;
4. Written informed consent provided

Exclusion criteria

1.  Patients who are unable to comply with study procedures and follow up

Locations

Netherlands Cancer Institute
Amsterdam, Netherlands
Contact: N. Steeghs, MD, PhD
Principal Investigator: N. Steeghs, MD, PhD

University Medical Center Groningen
Groningen, Netherlands
Contact: A. K.L. Reyners, MD, PhD +31 50 361 6161 a.k.l.reyners@umcg.nl
Contact: R. Bleckman, MD +31 50 361 6161
Principal Investigator: A. K.L. Reyners, MD, PhD

LUMC
Leiden, Netherlands
Contact: A. J Gelderblom, MD, PhD
Principal Investigator: A J Gelderblom, MD, PhD

Radboud UMC
Nijmegen, Netherlands
Contact: I. Desar, MD, PhD
Principal Investigator: I. Desar, MD, PhD

Erasmus MC
Rotterdam, Netherlands
Contact: R HJ Mathijssen, MD, PhD
Principal Investigator: R HJ Mathijssen, MD, PhD

Contact

A. K.L. Reyners, MD, PhD +31 50 361 6161 a.k.l.reyners@umcg.nl
R.F Bleckman, MD +31 50 361 6161 r.f.bleckman@umcg.nl

Full description

This is a multi-centre, open label, randomized phase 3 selection study (1:2:2 randomization).

After confirmation of the eligibility criteria, 185 patients will be randomized 1:2:2 to either the control arm (doxorubicin 60-75 mg/m² IV every 3 weeks) or experimental arm 1 (doxorubicin 12 mg/m2 IV every week) or experimental arm 2 (cyclophosphamide 100 mg orally BD plus prednisolone 10-20 mg orally on day 1 to day 7 of each 14 day cycle).

Health-related quality of life (HRQoL) assessment will be performed every 3 weeks during the first 12 weeks and every 12 weeks thereafter until month 12 after start of treatment.

Disease evaluation will be performed every 12 weeks until progression. The primary endpoint of the study is difference among the study arms in physical and role functioning at 12 weeks.

Inclusion criteria

1. Histologically proven advanced unresectable or metastatic soft tissue sarcoma
2. Representative formalin fixed, paraffin embedded tumor blocks or a minimum of 10 unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send at least 10 unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial.
3. Age ≥ 65 years of age (patients between 65 and 69 years old are eligible if G8 score ≤ 14; patients ≥ 70 years old are eligible independent of G8 score)
4. WHO performance status 0 – 2
5. Life expectancy based on other significant morbidity of ≥ 6 months
6. Presence of measurable disease (according to RECIST 1.1), as confirmed by imaging within the 28 days prior to randomization. CT with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT + MRI.
7. Progressive disease at entry based on RECIST 1.1
8. Patients amenable to receive doxorubicin according to investigator’s assessment
9. Adequate haematological and organ function assessed prior to randomization:
10. Haematological function:

• • Haemoglobin ≥ 9.0 g/dL or 5.6 mmol/L
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Coagulation: partial thromboplastin time (PTT) ≤ 1.0 times upper limit of normal (1.0 x ULN) of institutional limits and prothrombin time (PT) ≤ 1.0 x ULN of institutional limits

11. Renal function: estimated glomerular filtration rate (eGFR) > 50 ml/min/m2 (calculated by the MDRD formula in appendix E); no proteinuria ≥ grade 2 (CTCAE version 5.0);

12. Hepatic function: bilirubin ≤ 1.0 x ULN of institutional limits, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤1.5 x ULN.

If isolated elevated bilirubin <2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved.

13. Cardiac function: clinically normal function based on the institutional lower limit of normal for left ventricular ejection fraction (LVEF) as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead electrocardiogram (ECG) without clinically relevant abnormalities. Measurement should include investigator assessment of a potential participant’s risk for heart failure with a validated clinical classification system, i.e. the New York Heart Association Functional Classification. Only patients with NYHA class 1 and 2 according to appendix D are eligible.

13. Completion of EORTC QLQ-C30 and EORTC QLQ-ELD14 at baseline.

14. Assessment of G8 geriatric screening tool

15. Assessment of Katz Index of Independence in Activities of Daily Living (ADL)

16. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

17. With female partners of childbearing potential, men must remain abstinent or use a condom during the treatment period and for a period of 6 months after the last dose of doxorubicin-based chemotherapy and for a period of 12 months after the last dose of cyclophosphamide-based chemotherapy. Men must refrain from donating sperm during this same period. Contraception should be considered for the female partners of childbearing potential as well.

18. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for a period of 6 months after the last dose of doxorubicin-based chemotherapy and for a period of 12 months after the last dose of cyclophosphamide-based chemotherapy to avoid exposing the embryo.

19.Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations including commitment to completing questionnaires during the course of the study.

Exclusion criteria

1. Symptomatic or known brain metastasis
2. Any prior treatment with anthracyclines
3. Any prior systemic treatment for metastatic STS
4. Inability to swallow and/ or retain oral tablets
5. Rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
6. Hypersensitivity to doxorubicin, cyclophosphamide, prednisolone or to any of their metabolites or to any of their excipients
7. Uncontrolled severe illness, including but not limited to:
8. Congestive heart failure
9. Angina pectoris
10. Acute inflammatory heart disease
11. Myocardial infarction within 1 year before randomization
12. Arterial hypertension defined as blood pressure ≥ 150/100 mm Hg despite optimal medical therapy
13. Uncontrolled cardiac arrhythmia
14. Increased haemorragic tendency
15. Uncontrolled diabetes
16. Bone marrow aplasia
17. Psychosis
18. Active or uncontrolled infections among which those requiring systemic antibiotics or antimicrobial therapy.
19. Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow.
20. Vaccination with live vaccines within 30 days prior to study entry
21. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial.
22. Known contraindication to imaging tracer or contrast medium and contraindication to MRI
23. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and its active requirements (including completion of questionnaires) and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial

Full description

This is a multicenter, randomized, open label phase lll trial to assess whether preoperative chemotherapy, as an adjunct to curative-intent surgery, improves the prognosis of high risk DDLPS (dedifferentiated Liposarcoma) and LMS (Leiomyosarcoma) patients as measured by disease free survival.

After confirmation of eligibility criteria, patients will be randomized to either the standard arm or experimental arm.

Inclusion criteria

1. Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of retroperitoneal space or infra-peritoneal spaces of pelvis.
2. LMS:
   • Grades 2 and 3 of LMS can be included
   • Minimum size of LMS tumor should be 5 cm
3. LPS:
   • Diagnosis should be confirmed based on MDM2 (Mouse double minute 2 homolog) and CDK4 (Cyclin-dependent kinase 4) expression on IHC (immunohistochemistry), while proof of MDM2 amplification is highly recommended.
   • All grade 3 DDLPS can be included.
   • DDLPS with confirmed grade 2 on biopsy can be included when:
     • The grade 2 DDLPS has an FNCLCC score=5 (Fédération Nationale des Centres de Lutte Contre Le Cancer), has no necrosis on the biopsy but clear necrosis on imaging.
     • The tumors carry a high risk gene profile as determined by the Complexity INdex in SARComas (CINSARC-high)
4. Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides must be available at baseline for histological central review.
5. Unifocal tumor
6. Absence of extension through the sciatic notch or across the diaphragm
7. Resectable tumor: resectability is based on pre-operative imaging (CT-abdomen, potentially also with MRI) and has to be defined by the local treating sarcoma team. A patients is not considered resectable when the expectation is that only an R2 resection is feasible.
   • Criteria for non-resectability are:
     • Involvement of the superior mesenteric artery, aorta, coeliac trunk and/or portal vein
     • Involvement of bone
     • Growth into the spinal canal
     • Progression of retro-hepatic inferior vena cava leiomyosarcoma towards the right atrium
     • Infiltration of multiple major organs like liver, pancreas and/or major vessels
8. Tumor not previously treated (no previous surgery (excluding diagnostic biopsy), radiotherapy or systemic therapy)
9. Patient must have radiologically measurable disease (RECIST 1.1), as confirmed by imaging within the 28 days prior to randomization. CT thorax abdomen pelvis with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT thorax + MRI abdomen & pelvis.
10. ≥ 18 years old (no upper age limit)
11. WHO (World Health Organization) performance status ≤ 2
12. Adequate haematological and organ function:
    • Haematological: haemoglobin > 9.0 g/dL or 5.6 mmol/L, absolute neutrophils > 1.5 x 109/L, platelets > 100 x 109/L Note: Platelet transfusions is allowed to achieve these baseline values
    • Renal: estimated glomerular filtration rate (eGFR) > 50 ml/min/m2; No proteinuria CTCAE ≥ grade 2;
    • Hepatic: Bilirubin ≤ 1.0 times upper limit of normal (1.0xULN) of institutional limits, ALT (alanine aminotransferase) and/or AST (aspartate transaminase) ≤1.5 x ULN. If isolated elevated bilirubin <2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved.
    • Heart: Clinically normal cardiac function based on left ventricular ejection fraction (LVEF ≥ 50%) as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead ECG without clinically relevant abnormalities.
13. American Society of Anesthesiologist (ASA) score < 3
14. Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment or surgery.

Note: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post menopausal unless permanently sterile.

Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

15. Patients of childbearing / reproductive potential should use highly effective birth control             measures, as defined by the investigator, during the study treatment period and for at                   least 6 months after the last dose of treatment or date of surgery. A highly effective                         method of birth control is defined as a method which results in a low failure rate (i.e. less             than 1% per year) when used consistently and correctly. Such methods include:

1. • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
   • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
   • Intrauterine device (IUD)
   • Intrauterine hormone-releasing system (IUS)
   • Bilateral tubal occlusion
   • Vasectomized partner
   • Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)

16. Female subjects who are breast feeding should discontinue nursing prior to the first day of study treatment and until 6 months after the last study treatment.
17. Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion criteria

1. Sarcoma originated from bone structure, abdominal or gynecological viscera
2. Metastatic disease
3. Tumors with extension through the sciatic notch or across the diaphragm
4. Hypersensitivity to doxorubicin, ifosfamide, dacarbazine or to any of their metabolites or to any of their excipients
5. Persistent myelosuppression
6. Myocardial infarction within the last 6 months
7. Uncontrolled cardiac arrhythmia
8. Previous treatment with maximum cumulative doses (450mg/m² Doxorubicin or equivalent 900mg/m² EpiADM) of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones
9. Active and uncontrolled infections
10. Vaccination with live vaccines within 30 days prior to study entry
11. Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow.
12. Other invasive malignancy within 5 years, with the exception of adequately treated non-melanoma skin cancer, localized cervical cancer, localized and presumably cured prostate cancer.
13. Uncontrolled severe illness, infection,medical condition (including, uncontrolled diabetes or hypertension), other than the Primary LPS or LMS of the retroperitoneum.
14. Female patients who are pregnant or breastfeeding or female and male patients of reproductive potential who are not willing to employ effective birth control method.
15. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial
16. Known contraindication to imaging tracer and to MRI

Full description

Currently, there is no consensus about the optimal treatment for patients with high grade soft tissue sarcomas (STS) which are localized in the extremities. To ensure overall survival, there is a tendency to operate with wide resection margins, but this has a high impact on quality of life especially when limb function must be sacrificed. (Neo)adjuvant radiotherapy allows for narrower surgical margins but is associated with significant short -and long-term side-effects. As evidence on the best treatment is lacking, treatment choice for individual patients should be driven by their weighing of the benefits and harms of the treatment options in light of their personal situation.
However, current treatment decision-making in STS care is one-size fits all, and not informed by individualized risks of treatment options and patients’ preferences. Consequently, there is no guarantee that patients with STS will receive treatment that is appropriate for their situation, and patients experience uncertainty about which treatment is best for their personal situation (decisional conflict).
From literature it is known that decision supporting interventions contribute to a better informed choice and less decisional conflict. Therefore, our research group developed a validated personalized risk assessment tool (Personalised Sarcoma Care: PERSARC) which provides patients and STS professionals insight into the personalized risks and benefits of each treatment option based on patient’s age, tumor size, tumor depth and histology in their decision-making process.
It is hypothesized that use of PERSARC leads to significantly less decisional conflict in patients and more informed decisions compared to usual care (treatment decisions without use of PERSARC) by reducing the uncertainty regarding risks and benefits of treatment options in high-grade extremity STS patients.

Inclusion criteria

Patients (>= 18 years) with primarily diagnosed (histologically confirmed) grade 2-3 extremity STS, who do not have a treatment plan yet and will be treated with curative intent. Patients with sarcoma subtypes or treatment options other than those mentioned in the PERSARC app are unable to participate. Furthermore, patients need to be Dutch fluency and literacy and mentally competent.

Exclusion criteria

1. Patient that are treated without curative intent
2. Patient that needs to be treated with chemotherapy or isolated limb perfusion
3. Patients were surgery is not indicated
4. Sarcoma subtypes not mentioned in the PERSARC app

Contact

Name: Anouk Kruiswijk
Email: a.a.kruiswijk@lumc.nl
Phone: 0631974532

Full description

The investigators will follow the EORTC QLG questionnaire development guidelines. First, a computerized search of the academic literature will be performed to identify all relevant HRQoL issues for and existing HRQoL questionnaires currently used among patients with sarcoma. In parallel, semi-structured interviews will be conducted worldwide with patients with sarcoma(N=179) and health care professionals (HCPs; N=35; phase 1a). The patient sample will be stratified to capture diversity across the sarcoma population tumour location (extremities, axial, head and neck, thorax, retroperitoneal/intra-abdominal and gynecological), stage (localized vs. metastatic disease ) and type or lines of treatment.

This list of HRQoL issues generated by the a) literature search, b) relevant items from the Item Library, and c) semi-structured patient and HCP interviews, and will be consolidated into a comprehensive list of issues for all languages of collaborating countries.

In phase 1b, the new list of HRQoL issues will be presented to another group of patients with sarcoma(N=475) and HCPs (N=72). Patients and HCPs will be asked to rate the HRQoL issues on relevance (4point Likert scale) and to prioritize the 10 most important issues.

Inclusion criteria

1. Age at diagnosis 18 years or older
2. Having a confirmed diagnosis of sarcoma

Exclusion criteria

1. Having any psychiatric condition or cognitive impairment that would hamper participation in interview/completion of self-reported questionnaires.
2. Patients with a Gastrointestinal Stroma Tumour (GIST) diagnosis, as they are quite unique in terms of type of disease and treatment.
3. Patients with Kaposi sarcoma, as this disease occurs quite often in people with AIDS
4. Patients with Carcinosarcoma as this disease is generally seen as a carcinoma

Full Description

To prospectively and retrospectively collect data of patients with bone or soft tissue sarcoma in the Netherlands to improve the knowledge and therefore the treatment care. Besides to create a continuous basis for a large variety of research purposes including prognostic and predictive research, health care policies and cost-effectiveness studies.

Inclusion criteria

1. Age ≥ 18 years
2. Histologically proven bone or soft tissue sarcoma, excluding Gastrointestinal Stromal Tumours

Exclusion criteria

1. Altered mental status that would prohibit the understanding of any giving of informed consent

Locations Netherlands

• Radboudumc
• Radiotherapiegroep

Contact

Name: dr. P.M. Braam
E-mail: p.braam@radboudumc.nl
Phone: +31-243614515
Address: Radboudumc, Geert Grooteplein Zuid 32, 6525 GA Nijmegen

Documenten:

Full description

Currently, soft tissue sarcomas (STS) are preoperatively irradiated in a conventionally fractionated regimen of 25 x 2 Gy in five weeks. Recent radiobiological investigations, however, suggest sensitivity to (modest) hypofractionation. Within this study, patients will be randomized to receive either the conventional schedule of 25 x 2 Gy or a shorter preoperative regimen of 14 x 3 Gy, in the hypothesis that both the postoperative wound complication rate until 30 days after surgery, as well as the local control probability at two years are comparable in both arms.

Inclusion criteria

1. Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma localized to the extremities, trunk and chest wall or the head and neck area, for which the standard treatment is a combination of and radiotherapy and surgery (deep seated and/or > 5cm in largest tumor diameter and/or an anticipated close resection margin and/or grade II/III according to the FNCLCC definition)
2. Absence of regional and/or distant disease. Patients staged by at least a CT scan of the chest (. Staging may also be performed by FDG-PET scanning and or total body MRI scans. Patients with an uncertain metastatic status (e.g. small indifferent lung nodules) and patients with a low metastatic burden not precluding the application of both preoperative radiotherapy and definitive surgery, are allowed to participate
3. WHO Performance Status ≤ 2
4. Able and willing to undergo preoperative radiotherapy
5. Able and willing to undergo definitive surgery
6. Able and willing to comply with regular follow-up visits
7. Able and willing to complete patient reported outcome questionnaires (health-related quality of life and cost effectiveness)
8. Able and willing to undergo randomization
9. Age ≥ 18 years

Exclusion criteria

1. Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma
2. Patients with recurrent sarcomas who underwent prior radiotherapy to the target lesion (if the primary sarcoma was managed by surgery only and no perioperative RT, patients are eligible)
3. Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), osteosarcomas
4. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
5. Female patients who are pregnant
6. Intention to perform an isolated limb perfusion, instead of a tumor resection
7. Neoadjuvant chemotherapy to be scheduled between end of radiotherapy and definitive surgery (neoadjuvant chemotherapy before radiotherapy is allowed)

Full description

The purpose of this study is to evaluate the overall response rate after 24 weeks of cemiplimab treatment in patients with locally advanced or metastatic secondary angiosarcomas

Inclusion criteria

1. Adult patient aged ≥ 18 years
2. Histologically confirmed diagnosis of progressive unresectable locally advanced or metastatic secondary angiosarcoma
3. Patients in the first line of systemic treatment unfit for chemotherapy and patients in advanced lines of systemic treatment
4. Measurable disease per RECIST 1.1 or per physical examination / daylight photography (WHO Offset Publication No. 48) as determined by the investigator]
5. Tumour tissue material available (archival or recent tumour biopsy)
6. WHO ECOG 0-2
7. Hepatic function:
   • Total bilirubin ≤ 1.5 x ULN (if liver metastases: ≤ 3 x ULN).
   • Transaminases ≤ 3 x ULN (if liver metastases: ≤ 5 x ULN).
   • Patients with Gilbert’s Disease and total bilirubin up to 3x ULN may be eligible after communication with and approval from the medical monitor
   • Alkaline phosphatase ≤ 2.5 x ULN (if liver OR bone metastases ≤5 x ULN)
8. Renal function: serum creatinine ≤ 2 x ULN or estimated CrCl > 30 mL/min.
9. Creatine phosphokinase (CPK) (also known as CK [creatine kinase]) elevation ≤ grade 2
10. Bone marrow function:
    • Hemoglobulin ≥ 9.0 g/dL
    • ANC ≥ 1.5 x 109/L
    • Platelet count ≥ 75 x 109/L
11. Expected life expectancy of at least 3 months as judged by the investigator

Exclusion criteria

1. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for irAEs. The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 Diabetes mellitus, residual hypothyroidism that required only hormone therapy, or psoriasis that does not require systematic treatment
2. Prior treatment with immune checkpoint inhibitors
3. Continuous immunosuppressive corticosteroid treatment (doses > 10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of cemiplimab. Note: patients who require a brief course of steroids (e.g. as prophylaxis for imaging studies) are not excluded
4. Active uncontrolled infection requiring therapy, including infection with HIV, active infection with HBV or HCV
5. History of pneumonitis within the last 5 years
6. Untreated brain metastasis(es) that may be considered active
   • Note in clarification: Patients with previously treated brain metastases may participate provided that the lesion(s) is (are) stable (without evidence of progression for at least 6 weeks on imaging obtained in the screening period), and there is no evidence of new or enlarging brain metastases, and the patients do not require any immunosuppressive doses of systemic corticosteroids for management of brain metastasis(es) within 28 days of the first dose of cemiplimab
7. Patients with allergy or hypersensitivity to cemiplimab or to any of the excipients must be excluded. Specifically, because of the presence of trace components in cemiplimab, patients with allergy or hypersensitivity to doxycycline or tetracycline are excluded
8. History of documented allergic reactions or acute hypersensitivity reaction attributed to antibody treatments
9. Patients with a history of solid organ transplant (patients with prior corneal transplants may be allowed to enroll after discussion with and approval from the medical monitor)
10. Any anticancer treatment other than radiation therapy (chemotherapy, targeted systemic therapy, imiquimod, photodynamic therapy), investigational or standard of care, within 30 days of the initial administration of cemiplimab or planned to occur during the study period
11. Receipt of live vaccines (including attenuated) within 30 days of first study treatment
12. Prior use of PI3K-D inhibitors
13. Women of childbearing potential (WOCBP)*, or sexually active men, who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment prior to the start of the first treatment, during the study, and for at least 6 months after the last dose.
14. Breastfeeding
15. Positive serum pregnancy test (a false positive pregnancy test, if demonstrated by serial measurements and negative ultrasound, will not be exclusionary, upon communication with and approval from the medical monitor)
16. Any other condition that might interfere with experimental treatment and the study procedures as judged by the investigator