A Phase 2, single arm study on dacarbazine (DTIC) followed by immunotherapy re-challenge in unresectable or metastatic melanoma with primary resistance to PD-1/PD-L1 or PD-1 + CTLA-4 blockade (PROMIT: PReconditioning of TumOr, Tumor Microenvironment and the Immune System to ImmunoTherapy)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Erlangen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Jan 2020 → 15 Jan 2026

Decision date (initial)

2024-11-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Deutsche Krebshilfe

External identifiers

EU CT number

2024-517065-16-00

EudraCT number

2017-003556-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

Dacarbazine (DTIC) chemotherapy sensitizes metastatic melanoma towards immunotherapy
First primary objective: Improvement of the overall response rate
Second primary objective: Increase of the overall survival (OS)

Secondary objectives 2

1. Collect biological samples (tissue/blood/stool) to assess immunological changes
2. Quality of life

Conditions and MedDRA coding

Melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
2. Pretreated, histologically confirmed unresectable Stage III or Stage IV melanoma, as per AJCC staging system.
3. Patients must have received anti-PD-1/PD-L1 or combined CTLA-4/PD-1 blockade for unresectable stage III or stage IV melanoma. Patients must have shown primary resistance to ICB regimen defined as progressive disease (RECIST 1.1) without prior response (partial or complete remission as defined by RECIST 1.1) to the same regimen.
4. Measurable disease by CT or MRI per RECIST 1.1 criteria
5. Tumor tissue from an unresectable or metastatic site of disease must be obtainable during screening as well as during the ICB phase.
6. BRAF wildtype as per regionally acceptable V600 mutational status testing. BRAF mutant subjects and those with indeterminate or unknown BRAF status are not permitted to be enrolled.
7. Prior palliative radiotherapy must have been completed at least 2 weeks prior to study drug administration.
8. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization: WBC ≥ 3000/uL; Neutrophils ≥ 1500/uL; Platelets ≥ 100x103/uL; Hemoglobin > 9.0 g/dL; Creatinine Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min; AST/ALT ≤ 3 x ULN (≤ 5 x ULN for subjects with liver metastases); Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
9. Subject re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been randomized/ has not been treated). If re-enrolled, the subject must be re-consented.
10. Men and women, age ≥ 18 years
11. Women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 3. DTIC is teratogenic. There is an insufficient amount of information to assess teratogenicity for ICB. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP should perform contraception for 6 months after the last dose of ICB.
12. Women of child bearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of investigational product.
13. Women must not be breastfeeding
14. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (see Appendix 3). The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half- life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half-lives. Therefore, contraception has to be performed for 8 months after the last dose of ICB.
15. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile; see Section 3.2.3 for the definition of WOCBP) and azoospermic men do not require contraception.

Exclusion criteria 16

1. Active (symptomatic) brain metastases or leptomeningeal metastases. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. Patients with asymptomatic brain metastases not receiving > 10 mg/day prednisone equivalents can be enrolled.
2. Uveal or mucosal melanoma. Patients with conjunctival melanoma can be enrolled.
3. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration (e.g. epilepsy with the intake of phenytoin), impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results (e.g. severe leucopenia/thrombocytopenia, severe liver or renal disorders).
4. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
5. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism, adrenal or pituitary insufficiency due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
6. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of DTIC administration. Inhaled or topical steroids, and adrenal replacement doses >10 mg daily prednisone equivalents, are permitted in the absence of active autoimmune disease.
7. Any major surgery (e.g., hip or spine surgery) less than 28 days prior to the first dose of DTIC.
8. Uncontrolled adrenal insufficiency.
9. Known history of testing positive for active Hepatitis B or Hepatitis C infections.
10. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
11. History of allergy to study drug components.
12. History of severe hypersensitivity reaction to DTIC, pembrolizumab, nivolumab or ipilimumab.
13. WOCBP who are pregnant or breastfeeding
14. Women with a positive pregnancy test at enrollment or prior to administration of study medication.
15. Prisoners or subjects who are involuntarily incarcerated.
16. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Overall response rate (ORR) at week 14 according to RECIST 1.1 in all patients receiving at least on. A patient is defined as responder if a complete response (CR) or partial response (PR) can be seen. A patient with stable disease (SD) or progressive disease (PD) will be defined as non-responder.
2. Overall survival (OS), defined as the time between study inclusion and date of death (any cause).

Secondary endpoints 2

1. Collect biological samples (tissue/blood/stool) to assess immunological changes
2. Quality of life assessed by EORTC QLQ-C30

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Erlangen AöR

Sponsor organisation

Universitaetsklinikum Erlangen AöR

Address

Maximiliansplatz 2, Innenstadt Innenstadt

City

Erlangen

Postcode

91054

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Erlangen AöR

Contact name

Prof. Dr. med. Lucie Heinzerling

Public contact point

Organisation

Universitaetsklinikum Erlangen AöR

Contact name

Prof. Dr. med. Lucie Heinzerling

Third parties 1

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications